Natural Alternatives to Long‐Term NSAID Use

Krista J. Clark, PT, FAAOMPT Wellspring Physical Therapy Midway, Utah AAOMPT 2010 AAlnnual CfConference I have long been interested in integrative healthcare. I see the pendulum swinging to a balance point of approaches that work with modern science and, by science, understanding how the natural age‐old wisdom is useful. As manual physical therapists, because our treatment is natural, we have the knowledge and abilities to bridge these approaches. The focus of this presentation is on delivering information and resources that we as physical therapists can give to patients to improve self advocacy. I have long viewed my roll as a provider of information and data so that people can educate themselves and make more informed decisions regarding their health care. I make this clear to people when these topics are discussed in my clinic. NSIADs

• Aspirin, derived from white willow bark has been used since ancient times. Use has been documented as early as 1763. • Indomethicine was released in the 1960s. Ibuprofen as Brufen was released in 1969. • 1988 COX‐2 was indentified in Provo UT. • Action: inhibits prostaglandins • In 1999 16,685 deaths from NAID toxicity, (close to numbers of deaths from Leukemia and AIDS). • Up to 40% of people will have detectable gastric ulcers or some form adverse GI reactions. • Economics: 2001‐$4.8 billion in prescribed drugs and $3 billion OTC analgesics (Includes acetaminophen) were sold. (Laine, Gastroenterology 2001 120:594 ) • Vioxx sales halted in 2004. Data on COX‐2 cardiovascular events was apparent by 2005.

• Sean Whelton, MD Georgetown University Hospital Feb. 13, 2009 Effects of antiinflammatory drugs on the progression of osteoarthritis of the knee. LINK Study Group. Longitudinal Investigation of Nonsteroidal Antiinflammatory Drugs in Knee Osteoarthritis. Huskisson EC, Berry H, Gishen P, Jubb RW, Whitehead J. Department of Rheumatology, St. Bartholomew's Hospital, London, UK. J Rheumatol. 1995 Oct;22(10):1941‐6.

¾ 812 patients randomized double blind parallel group ¾ Patients received either indomethacin (Indocin) 25 mg three times daily, tiaprofenic acid (an NSAID, Surgam in the UK) 300 mg twice daily, or matched placebo. ¾ Joint space narrowing was measured by a 6 point grading scale, using radiographs taken with a standardized technique at recruitment and annually thereafter. ¾ RESULTS: Three hundred and seventy six patients completed at least one year of study medication and therefore contributed evaluable results. More than twice as many patients showed deterioration in the indomethacin group as in the placebo group; of 170 available patients at the 3rd interim analysis, 40 of 85 receiving indomethacin had deteriorated compared to 19 of 85 receiving placebo, a statistically significant difference (p = 0. 009). ¾ No statistically significant difference (p = 0.308) was found between tiaprofenic acid and placebo at the 7th interim analysis, the conclusion of the study. ¾ CONCLUSION: Indomethacin increased the rate of radiological deterioration of joint space in patients with OA of the knee; tiaprofenic acid dddid not. The long‐term effects of non‐steroidal anti‐inflammatory drugs in osteoarthritis of the knee: a randomized placebo‐controlled trial D. L. Scott, H. Berry, H. Capell, J. Coppock, et. al. Rheumatology 2000; 39: 1095‐1101© 2000 British Society for Rheumatology

¾ A parallel‐group, randomized, single‐blind trial of patients with knee OA recruited 812 patients from 20 centres; 307 patien ts receidived tiapro fen ic acid (300 mg bbd).d.), 202 iidndome thithacin (25 mg tdt.d.s. ) and 303 matching placebo for up to 5 yr. ¾ At the end of the parallel‐group study, patients receiving tiaprofenic acid or placebo entered a 4‐week blinded cross‐over study of tiaprofenic acid or placebo, both given for 2 weeks. ¾ Assessments were at blibaseline, 4 weeks, then at 6‐month iilntervals for up to 5 yr in the paralle l group study and at 2‐week intervals in the cross‐over study. They comprised pain scores, duration of morning stiffness, patients' global assessments, paracetamol consumption, adverse reactions, withdrawals and functional outcomes. ¾ There were siifitignificant fllfalls in overall pain scores in patien ts receiiiving NSAIDs compared with plblacebo at 4 weeks in the parallel‐group phase. Thereafter there were no advantages favouring active therapy. ¾ In the cross‐over phase, pain scores were significantly lower in patients receiving tiaprofenic acid than placebo. ¾ Potentially severe side‐effects were rare; for example, there were only three cases of gastrointestinal bleeding on NSAIDs. ¾ Conclusions. NSAIDs significantly reduce overall pain over 4 weeks. This short‐term responsiveness is retained, and even after several years of therapy with tiaprofenic acid pain scores increased over 2 weeks when it was chdhanged to plblacebo. ¾ Our results do not show long‐term benefits from the use of NSAIDs in OA and the majority of patients had persisting pain and disability despite therapy. Rheumatology 2000; 39: 1095‐1101, continued Patients who remained on treatment for 12 months or longer not only showed no measurable benefit from active treatment but also had a static clinical picture with unchanging pain levels and durations of morning stiffness (Fig. 2) Is there an association between the use of different types of nonsteroidal antiinflammatory drugs and radiologic progression of osteoarthritis? The RRttdotterdam Stud y. Reijman M, Bierma‐Zeinstra SM, Pols HA, Koes BW, Stricker BH, Hazes JM. Arthritis Rheum. 2005 Oct;52(10):3137‐42.

¾ 1,695 subjects were analyzed, (2,514 hips) and 635 subjects (874 knees) ages 55 years and older from the Rotterdam Study ¾ radiographs of the hip and knee at baseline and followup (mean followup time 6.6 years) were evaluated. ¾ Radiologic OA (ROA) progression was defined as a minimu m increase of 1 in the Kellgren/Lawrence grade or incident joint replacement at followup. ¾ The associations between the different types of NSAIDs and progression of ROA were assessed using multivariate logistic regression analysis. ¾ RESULTS: Those subjects who were receiving diclofenac (Voltaren) >180 days had a 242.4‐ fold increased risk (95% confidence interval [95% CI] 1.0‐6.2) of progression of hip ROA ¾ 3.2‐fold increased risk (95% CI 1.0‐9.9) of knee ROA, compared with those considered short‐term users (diclofenac for 1‐30 days). ¾ These associations were adjusted for age, sex, body mass index, baseline ROA, followup time, and defined daily dosage. ¾ CONCLUSION: These data suggest that diclofenac may induce accelerated progression of hip and knee ROA. ¾ Whether this occurs because of a true deleterious effect on cartilage or because of excessive mechanical loading on a hip following pain relief remains to be investigated. Differential direct effects of cyclo‐oxygenase‐1/2 inhibition on proteoglycan turnover of human osteoarthritic cartilage: an in vitro study. Mastbergen SC, Jansen NW, Bijlsma JW, Lafeber FP. Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht, The Netherlands. Arthritis Res Ther. 2006;8(1):R2.

¾ Comparison of the direct effects of indomethacin, naproxen, aceclofenac and celecoxib on matrix turnover in human OA cartilage tissue. ¾ Human clinically defined OA cartilage from five different donors was exposed for 7 days in culture to indomethacin, naproxen, aceclofenac and celecoxib‐‐agents chosen based on their cyclo‐ oxygenase (COX)‐2 seliilectivity. ¾ As a control, SC‐560 (a selective COX‐1 inhibitor) was used. ¾ Changes in cartilage proteoglycan turnover and prostaglandin E2 production were determined. ¾ OA cartilage exhibited characteristic proteoglycan turnover. Indomethacin further inhibited protlteoglycan synthes is; no siiifitgnificant effec t of iidndome thithacin on prottleoglycan release was ffdound, and proteoglycan content tended to decrease. ¾ Naproxen treatment was not associated with changes in any parameter. ¾ In contrast, aceclofenac and, prominently, celecoxib had beneficial effects on OA cartilage. Both were associated with increased proteoglycan synthesis and normalized release. Importantly, both NSAIDs improved proteoglycan content. ¾ Selective COX‐1 inhibition resulted in adverse effects on all parameters, and prostaglandin E2 production was only mildly inhibited. ¾ NSAIDs with low COX‐2/COX‐1 selectivity exhibit adverse direct effects on OA cartilage, whereas high COX‐2/COX‐1 selective NSAIDs did not show such effects and might even have cartilage reparative properties. Diacerein has a weak effect on the catabolic pathway of human osteoarthritis synovial fibroblast‐‐comparison to its effects on osteoarthritic chondrocytes. Alvarez‐Soria MA, Herrero‐Beaumont G, Sánchez‐Pernaute O, Bellido M, Largo R. Joint and Bone Research Unit, Rheumatology Department,, Avenida Reyes Católicos 2, 28040 Madrid, Spain. Rheumatology (Oxford). 2008 May;47(5):627‐33. Epub 2008 Mar 27 ¾ OBJECTIVES: Synoviocytes play a crucial role in the inflammatory response leading to structural damage in OA. Our aim was to assess the effects of diacere in and NSAIDs on cellular responses of synoviocytes associated with inflammation and structural integrity of cartilage in OA. ¾ METHODS: The effects of diacerein, celecoxib, diclofenac, meloxicam and indomethacin on prostaglandin (PG) E2 production, cyclo‐oxygenase‐2 (COX‐2) protein expression, nitrite levels, presence of MMP‐1 and ‐13, and activation of nuclear factor‐kappaB (NF‐kappaB) were studied on stimulated OA synoviocytes and chondrocytes. ¾ RESULTS: Diacerein and NSAIDs inhibited IL‐1beta‐stimulated NF‐kappaB activation in synoviocytes and chondrocytes except indomethacin in synoviocytes. Diacerein further increased COX‐2 protein expression and PGE2 synthesis in synoviocytes stimulated with IL‐ 1beta, while no effect was observed on stimulated chondrocytes. NSAIDs diminished until almost basal levels PGE2 release in both cells and, surppgyrisingly, these drugs also diminished COX‐2 protein expression both in synoviocytes and chondrocytes. With regard to structural mediators, diacerein decreased MMP‐13 levels in synoviocytes but did not modify MMP‐1 presence. NSAIDs induced a significant increase in MMP‐1 levels in both cell types and in MMP‐13 levels in chondrocytes. ¾ CONCLUSIONS: Diacerein does not seem to reduce but rather increase inflammatory mediators in synoviocytes, while it does not overall affect chondrocyte inflammatory profile. Rheumatology (Oxford). 2008 May;47(5):627‐33. Epub 2008 Mar 27, continued

¾Progressive degradation of the extracellular matrix that comprises joint tissues is a major feature in OA leading to permanent loss of function. Major enzymes involved in the process are MMPs that are able to degrade some of the components of the extracellular matrix. Collagenase 1 (MMP‐1) and collagenase3 (MMP‐13) are involved in cartilage collagen II degradation in OA. In our experiments, diacerein diminished MMP‐13 levels in synoviocytes, although it did not modify MMP‐1 levels in both the cells tested and MMP‐13 protein expression in chondrocytes. ¾NSAIDs induced a statistically significant increase in MMP‐1(protein expression ) levels in synovial fibroblasts and chondrocytes, and in MMP‐13 levels in chondrocytes. Previous in vitro studies have demonstrated that PGE2 depletion could activate cellular catabolism by enhancing MMP synthesis in synovial fibroblasts. These results may explain the lack of retardation of cartilage destruction despite the favourable profile of NSAIDs in controlling pro‐inflammatory pathogenetic routes. ¾The release of PGE2 at high concentrations to the inflammatory site would contribute to increase inflammation‐related pain. However, diacerein has been shown to relieve chronic pain in knee and hip OA. PGE2 may act as a dual mediator, on one hand supporting disease progression by enhancing the proteoglycan degradation, and on the other hand by down‐ regulating the expression and synthesis of cytokines. On the whole, these actions could indicate that either excessive or sub‐physiological PGE2 levels are undesirable, a hypothesis that has been already approached by our group and other authors. Indomethacin and Celecoxib Impair Rotator Cuff Tendon‐to‐Bone Healing David B. Cohen, MD, Sumito Kawamura, MD, John R. Ehteshami, MD, and Scott A. Rodeo, MD October 6, 2005, doi: 10.1177/0363546505280428 Am J Sports Med March 2006 vol. 34 no. 3 362‐369

¾ Study Design: Controlled laboratory study. ¾ Methods: One hundred eighty Sprague‐Dawley rats underwent acute rotator cuff repairs. Postoperatively, 60 rats received 14 days of celecoxib, a cyclooxygenase‐2– specific nonsteroidal anti‐inflammatory drug; ¾ 60 received indomethacin, a traditional nonselective nonsteroidal anti‐inflammatory drug; and 60 received standard rat chow ¾ Animals were sacrificed at 2, 4, and 8 weeks and evaluated by gross inspection, biomechanical testing, histologic analysis, and polarized light microscopy to quantify collagen formation and maturation. ¾ RltResults: Five tdtendons compltlletely fildfailed to hlheal (4 celiblecoxib, 1 idindome thi)thacin). There were significantly lower failure loads in the celecoxib and indomethacin groups compared with the control groups at 2, 4, and 8 weeks (P < .001), with no significant difference between nonsteroidal anti‐inflammatory drug groups. There were significant differences in collagen organization and maturation between the controls and both nonsteroidal anti‐inflammatory drug groups at 4 and 8 weeks (P < .001). Controls demonstrated progressively increasing collagen organization during the course of the study (P < .001), whereas the nonsteroidal anti‐inflammatory drug groups did not. ¾ Conclusion: Traditional and cyclooxygenase‐2–specific nonsteroidal anti‐inflammatory drugs significantly inhibited tendon‐to‐bone healing. This inhibition appears linked to cyclooxygenase‐2. The Effects of Common Anti‐Inflammatory Drugs on the Healing Rat Patellar Tendon Scott T. Ferry, MD, Laurence E. Dahners, MD, Hessam M. Afshari, and Paul S. Weinhold, PhD Copyright 2007 by American Orthopaedic Society for Sports Medicine Presented at the interim meeting of the AOSSM, Chicago, Illinois, March 2006

¾ A total of 215 Sprague‐Dawley rats underwent transection of the patellar tendon at the inferior pole of the patella, which was subsequently stabilized with a cerclage suture. The animals were then randomized into 7 groups and administered 1 of the following analgesics for 14 days: ibuprofen, acetaminophen, naproxen, piroxicam, celecoxib, valdecoxib, or control. At 14 days, all animals were sacrificed, and the extensor mechanism was isolated and loaded to failure. Biochemical analysis of the repair site tissue was performed. Animal activity throughout the study was monitored using a photoelectric sensor system. ¾ The control group demonstrated greater maximum load compared with the celecoxib, valdecoxib, and piroxicam groups (P < .05). The acetaminophen and ibuprofen groups were also significantly stronger than the celecoxib group (P < .05) but not statistically different than the control group. A total of 23 specimens had failure of the cerclage suture with the following distribution: control (0/23), ibuprofen (0/23), acetaminophen (0/24), naproxen (3/24), piroxicam (4/24), celecoxib (6/22), and valdecoxib (10/24). The difference in distribution of the failures was significant (P < .001). ¾ Anti‐inflammatory drugs, with the exception of ibuprofen, had a detrimental effect on healing strength at the bone‐tendon junction as demonstrated by decreased failure loads and increased failures of the cerclage suture. Acetaminophen had no effect on healing strength. The biomechanical properties paralleled closely with the total collagen content at the injury site, suggesting that these agents may alter healing strength by decreasing collagen content. Selective and nonselective cyclooxygenase (COX) inhibitors should be used judiciously in the acute period after injury or surgical repair at the bone‐tendon junction. NSAIDs and spinal fusion The effect of postoperative nonsteroidal anti‐inflammatory drug administration on spinal fusion. SD Glassman et al. Spine 1998 23: 834‐838. Review from Bandolier • The effect of ketorolac (Toradol) after spinal fusion was studied in a retrospective review of 288 cases [14] in a single centre. Patients had posterior spinal fusion between 1991 and 1992, and there was a minimum two‐year follow up. Ketorolac was administered as a 60 mg intramuscular loading dose followed by 30 mg every 6 hours as needed. Seven patients given ketorolac had 2‐20 (mean 8) additional 10 mg oral doses as needed. • Ketorolac was given to 167 patients, and no NSAID to 121. Patients having ketorolac received between one and 39 doses (mean 10) of ketorolac after surgery. The two groups were demographically similar. • Nonunion occurred in 5/121 (4%) of patients having no NSAID and 29/167 (17%) of those receiving ketorolac. The odds ratio was 4.9 (1.8 to 17). The same degree of increased risk was seen in all subgroups. There was a dose‐dependent relationship between nonunion rates and ketorolac doses. • There was an apparent relationship between postoperative use of ketorolac and cigarette smoking. The nonunion rate was 2% in those who neither smoked nor had ketorolac, 7% for those who smoked but did not have ketorolac, 10% for nonsmokers having ketorolac and 25% for those who both smoked and had ketorolac. NSAIDs and spinal fusion Reuben SS. Considerations in the use of COX‐2 inhibitors in spinal fusion surgery. Anesth Analg 2001 93: 798‐804 & Effect of nonsteroidal anti‐inflammatory drugs on osteogenesis and spinal fusion. Reg Anesth Pain Med 2001 26: 590‐1. Review from Bandolier • Showed a low nonunion rate of 4.7% in 106 patients with postiterior spiilnal ffiusion tttdreated with roffibecoxib 50 mg postoperatively for five days. • Another analysis showed no difference in success rates for spilinal ffiusion bbtetween patien ts not tttdreated with NSAIDs and those treated with COX‐2 inhibitors rofecoxib or celecoxib in a retrospective study of 342 patients. There was no increase in non‐union rate with rofecoxib or celecoxib compared with non NSAID at about 5‐7%, but ketorolac (Toradol) was significantly worse at 19%. NSAIDs and fracture risk TP Van Staa et al. Use of nonsttidleroidal anti‐iflinflamma tory drugs and riiksk of ftfractures. Bone 2000 27: 563‐568. Review from Bandolier

• A large retrospective cohort study to examine NSAID use with fractures was conducted using the GPRD. It looked at fracture risk in people using NSAIDs and compared that with people who did not use NSAIDs. • Fracture rates with regular NSAID users were certainly not lower than controls. If anything, they were somewhat higher (Table 2) for vertebral and all nonvertebral fractures. Regular users had fracture rates no different from incidental users. Regular NSAID Control User Fracture Type # of Rate per # of Rate per Relative risk Fractures 100 yrs Fractures 100 yrs (95%CI) Vertebral 808 010.1 192 0030.03 292.9 (2. 5 to 334).4) All nonvertebral 10505 1.5 5793 1 1.5 (1.4 to 1.5) Forearm 2516 0.3 1556 0.3 1.3 (1.2 to 1.4) Hip 973 0.1 686 0.1 1.1 (0.98 to 1.2) NSAID Effects on Tissue Healing & Repair Summary References by Tim Watson • 33 studies & articles are cited • Date range 1980‐2000 • Most studies were done on rats and rabbits Showing • Inhibitory effects of non steroidal anti inflammatory drugs on musculoskeletal tissues healing and repair Effects of Nonsteroidal Anti‐Inflammatory Drugs on Bone Formation and Soft‐Tissue Healing Laurence E. Dahners, MD and Brian H. Mullis, MD, Department of Orthopaedics, University of North Carolina School of Medicine, Chapel Hill, NC J Am Acad Orthop Surg, Vol 12, No 3, May/June 2004, 139‐143. © 2004

Nonsteroidal anti‐inflammatory drugs continue to be prescribed as analgesics for patients with healing fractures even though these drugs diminish bone formation, healing, and remodeling. Inhibition of bone formation can be clinically useful in preventing heterotopic ossification in selected clinical situations. In this regard, naproxen may be more efficacious than the traditional indomethacin, and short‐term administration is as effective as long‐term. When fracture healing or spine fusion is desired, nonsteroidal anti‐inflammatory drugs should be avoided. Some nonsteroidal anti‐ inflammatory drugs have a positive effect on soft‐tissue healing; they stimulate collagen synthesis and can increase strength in the early phases of repair during skin and ligament healing. Cyclooxygenase‐2 inhibitors have an adverse effect on bone healing and may have an adverse effect on ligament healing. Therefore, further investigation is necessary to confirm that traditional nonsteroidal anti‐inflammatory drugs may be preferable for the healing of collagenous tissues. COX‐2 inhibitors and bone: 2005 update Prolonged use appears to interfere with bone healing By Stuart B. Goodman, MD, PhD, and Barbara D. Boyan, PhD AAOS Bulletin – June, 2005 ¾ Cyclooxygenase (COX) is an enzyme that controls the conversion of arachidonic acid, a phospholipid, to prostaglandins. Prostaglandins are ubiquitous molecules that have numerous effects on all cells in the body, including regulating bone ftiformation by ostbltteoblasts. ¾ COX‐1 is a “housekeeping” enzyme that regulates homeostatic activities in virtually all cells. It is particularly important in controlling platelet function, gastric acid secretion and renal blood flow. ¾ The COX‐2 enzyme is rapidly induced when the body is under systemic or local stress such as during shock, injury, infection or inflammation. Non‐specific NSAIDs inhibit both COX‐1 and COX‐2 activity, whereas COX‐2 inhibitors are more selective in their enzyme inhibition. ¾ There has been great controversy on the potential systemic adverse effects of COX‐ 2 inhibitors on the cardiovascular system. Indeed, two drugs, Vioxx (rofecoxib) and Bextra (valdecoxib), have been withdrawn from the USU.S. market. The remaining COX‐2 inhibitor on the market, Celebrex (celecoxib), has also undergone scrutiny. COX‐2 inhibitors and bone: AAOS 2005 update continued ¾In a follow‐up study, rofecoxib (Vioxx) given continuously for six weeks suppressed bone ingrowth; however, when the drug was given during the initial or final two weeks only of a six‐week treatment, bone ingrowth was only slightly (but not significantly) decreased compared to controls.20 This suggests reversibility of the adverse biological effects on bone when the drug is stopped. ¾In the October 2002 AAOS Bulletin, Thomas Einhorn, MD, wrote a timely article titled: “Use of COX‐2 inhibitors in patients with fractures. Is there a trade off between pain relief and healing?”1 Dr. Einhorn discussed the results of several animal studies that suggested that continuous usage of COX‐2 inhibitors may interfere with fracture healing. However, he also emphasized the paucity of clinical data in humans on this subject. ¾Prolonged use of these drugs probably interferes with key biological processes of osteoblasts. The adverse effects of short‐term use of NSAIDs and COX‐2 inhibitors are probably reversible when the drug is discontinued. However, the greater the exposure to NSAIDs (including COX‐2 inhibitors) during the first six weeks of fracture repair, bone ingrowth, spine fusion and related biological processes, the greater the negative effects. If suitable alternatives to NSAIDs are available, it may still be prudent to use the alternative and avoid the use of NSAIDs entirely in these conditions. Stuar t B. GdGoodman, MD, PhD, is a professor, dttdepartment of orthopae dic surgery at Stan for d UUinivers ity MdilMedical CtCenter, and a member of the AAOS Biological Implants Committee. Barbara D. Boyan, PhD, is a consultant to the Biological Implants Committee and is the Price Gilbert, Jr. Chair in Tissue Engineering in the department of biomedical engineering at Georgia Institute of Technology. We must look to where we have come from…

Park City Mountain Resort To see where we are going… BROMELAIN Excerpted from: THE HEALING POWER OF HERBS By Michael T. Murray, ND Prima Health Publishing, 1995

• Bromelain, obtained from the pineapple plant, (Anansus cosmosis) refers to a group of sulfur‐containing enzymes that digest protein (proteolytic enzymes or proteases). CilCommercial blibromelain is usually didderived from the stem, which differs from bromelain derived from the fruit. Bromelain was introduced as a therapeutic agent in 1957, since that time more than 200 scientific pppapers on its therapeutic applications have appeared in medical literature. • Dosage: The typical dosage of bromelain is 250 to 500 milligrams 3x day between meals. The dosage dddepends on the potency of the bromelain preparation, most currently available is in the 1,200‐1,800 mcu range. • Toxicity: Very large doses of bromelain have been given with no side effects. It is virtually nontoxic, as no LD (50%lethal dose)exists up to 10 grams per kilogram. BROMELAIN ‐ continued THE HEALING POWER OF HERBS By Michael T. Murray, ND

™ Bromelain reduces inflammation at first by breaking down fibrin ‐ fibrinolysis by stimulating the production of plasmin which breaks down fibrin thereby preventing fibrin from ppgroducing localized swelling. Plasmin blocks the formation of ppyroinflammatory compounds . ™ Ako H, Cheung AH, Matsuura PK. Isolation of a fibrinolysis enzyme activator from commercial bromelain. Arch Int Pharmacodyn Ther. 1981 Nov;254(1):157‐ 67. A possible role of prostaglandins and bdkiibradykininas a trigger of exudidation in carrageenan‐induced rat pleurisy. Agents Actions 8, 108‐112 1978 Katori M, et al

™Bromelain has been shown to reduce plasma kininogen levels resulting in inhibition of the production of kinins. Bromelain, a thilprotease from pineapple stem, depletes high molecular weight kininogen by activation of Hageman factor (factor XII) Sachiko Oh‐ishi, Yasuhiro Uchida, Akinori Ueno, Makoto Katori Department of Pharmacology, Kitasato University School of Medicine, Japan Thrombosis Research Volume 14, Issues 4‐5, 1979, Pages 665‐672 ™The site of action of bromelain in the kallikrein‐ kinin system was investigated by in vitro experiments which showed that normal human and rat plasma generated prekallikrein activator activity (active factor XII) as well as kinin after 10 min incubation with bromelain whereas Hageman factor ddfiieficient plasma did not. ™These results suggest that bromelain activates plasma prekkllkallikrein by activation of factor XII. Bromelain therapy in rheumatoid arthritis. Cohen A, Goldman J., Penn Med J. 1964;67:27–30. ™Bromelain was first reported to be of value as an analgesic/anti‐inflammatory for use in both rheumatoid arthritis and osteoarthritic patients in 1964. ™25 patients with severe RA, 1 with RA & OA, 2 with OA, 1 with gout were studied, who ™Had residual joint swelling following long‐term corticosteroid therapy and were given Bromelain and tapered steroids. Bromelain reduces mild acute knee pain and improves well‐being in a dose‐ dependent fashion in an open study of otherwise healthy adults. Walker AF, Bundy R, Hicks SM, Middleton RW Phytomedicine. 2002 Dec;9(8):681‐6 Hugh Sinclair Unit of Human Nutrition, The University of Reading, UK ™ There is preliminary clinical evidence to support the contention that the anti‐inflammatory and analgesic ppproperties of bromelain help to reduce syypmptoms of osteo‐ and rheumatoid arthritis. ™ The current study investigated the effects of bromelain on mild acute knee pain of less than 3 months duration in otherwise healthy adults. The study was an open, dose‐ranging postal study in volunteers who had been recruited through newspaper and magazine articles. ™ Two validated questionnaires (WOMAC knee health Index and the Psychological Well‐Being Index) were completed at baseline and after one month's intervention with bromelain, randomly allocated to volunteers as either 200 mg or 400 mg per day. ™ Seventy seven subjects completed the study. In both treatment groups, all WOMAC symptom dimension scores were siifitlignificantly reddduced compared with blibaseline, with redtiductions in the fina l bbttattery (to ta l symptom score) of 41 and 59% (P = 0.0001 and <0.0001) in the low and high dose groups respectively. ™ In addition, improvements in total symptom score (P = 0.036) and the stiffness (P = 0.026) and physical function (P = 0.021) dimensions were significantly greater in the high‐dose (400 mg per day) compared with the low‐dose group. ™ Compared to baseline, overall psychological well‐being was significantly improved in both groups after treatment (P = 0.015 and P = 0.0003 in the low and high dose groups respectively), and again, a significant dose‐response relationship was observed. ™ We conclude that bromelain may be effective in ameliorating physical symptoms and improving general well‐being in otherwise healthy adults suffering from mild knee pain in a dose‐dependant manner. Double blind, placebo‐controlled studies are now warranted to confirm these results. Systemic enzyme therapy in the treatment and prevention of post‐ traumatic and postoperative swelling. KikKamenicek V, HHlolan P, FFkranek P. Chirurg ic ke, Odde len i NNiemocnice, Bilovec. Acta Chir Orthop Traumatol Cech. 2001;68(1):45‐9. ™ PURPOSE OF THE STUDY: The authors concentrate on the use of enzyme therapy in traumatology. They monitored SET efficiency in the treatment and prophylazis of swelling in the postoperative period after the ilinternal fixat ion of fractures of long bones and compared it wihith the effect of standddard antiswe lling seu antioedematous drugs on the basis of aescin. MATERIAL: A group of 60 patients was followed after the fixation of long bones. The average age was 42 years (range, 12‐79 years). Fractures were treated by intrameduilary fixation or by external fixators. The patients were split into two groups. In 30 patients only Phlogenzym was administered for the treatment and prevention of posttraumatic and postoperative swelling. Another 30 patients‐‐the control group‐‐were treated by standard antioedematic drugs on the basis of aescin. The same analgesics were applied in both groups. METHODS: The group of patients with systemic enzyme therapy were treated by Phlogenzym in the dosage 3 times 3 tablets in the first three days after operation and subsequently 3 times 2 tablets in the remaining follow‐up period. In the postoperative period the changes of operated limb volume was monitored. The circumference of a limb was measured in the area of the largest oedema and 10 cm distally. Then the volume of this part of limb was calculated as the volume of conical frustum. The measurements were performed on postoperative days 1, 3, 5, 7, 10 and 14. The volume value of the 1st day was used as starting value (100%). The values of subsequent measurements were then compared to this starting value in both group of patients. Evaluation of the resorption of traumatic and postoperative haematoma and analgesis effect of Phlogenzym was also made. RESULTS: In the group of patients who were administered with Phlogenzym after operation the redtiduction of the posttraumati c and postttioperative swelling was continuous and significantly faster in compared with patients of the control group. A remarkable difference was revealed by the measurement on 5th postoperative day‐‐in patients treated by Phlogenzym the starting value of the volume of the operated in limb was reduced on average by almost 8%. In contrast, in the control group treated by standard drugs this value slightly increased above 100%. At the end of the first postoperative week the monitored volume was on average reduced by 12% in the SET group compared with 1.45% in the control group. At the end of the follow‐up‐‐on 14th postoperative day the volume was reduced in the SET group by almost 17% compared with 9% in the control group. Systemic enzyme therapy in the treatment and prevention of post‐traumatic and postoperative swelling. Continued ™ There was also an evidently good analgesic effect of the drug. The total consumption of analgesics of patients in the SET group was significantly lower, particularly in the early postoperative period. In the course of the follow‐up of both ggproups no marked differences were recorded in the changes of the volume of operated limbs in dependence on the method of fixation applied (intramedullary or external), sex of the patient or on the affected limb (lower or upper). The patients tolerated Phlogenzym very well, only one female patient suffered temporarily from poor digestion which, however, did not require to interrupt the administration of the drug. No other undesirable effects occurred. DISCUSSION: Fixation of long bones belongs to the most frequent operations in traumatological and orthopaedic departments of all levels. One of the factors which may have an unfavourable effect on the final result of fixation is a prolonged post‐trauma or pppostoperative swelling. The results of the study prove a clearly positive effect of system enzymotherapy on the reduction of oedema accompanying the trauma and inflammation. The study proved a statistical significance of the acceleration of the reduction of oedema in patients treated by Phlogenzym as compared to the control group treated by a standard antioedematous drugs. CONCLUSION: The authors verifie d tha t systitemic enzyme therapy could iflinfluence siifitlignificantly the results of traumatological surgery. Simple administration per os, efficient oedema reduction and thus accelerated healing, antiophlogistic and analgesic effect‐‐all these advantages justify the application of this therapeutic method what can be recommended as a part of the complex treatment in traumatology with both conservative and surgical approaches. Bromelain, the enzyme complex of pineapple (Ananas comosus) and its clinical application. An update Steven J. Taussig and Stanley Batkin, Department of Food Science and Human Nutrition, School of Troplcal Agriculture. University of Hawaii Cancer Research Center of Hawaii, University of Hawaii, Journal of Ethnopharmacology Volume 22, Issue 2, February‐March 1988, Pages 191‐ 203

• After a short description of the uses of pineapple as folk medicine by the natives of the tropics, the more important new pharmaceutical applications of bromelain, reported between 1975 and 1978, are presented. Alt houg h the exact chhilemical structure of all active components of bromelain is not fully determined, this substance has shown distinct pharmacological promise. Its properties include: (1) interference with growth of malignant cells; ()(2) inhibition of platelet aggregation; (3) fibrinolytic activity; (4) antiinflammatory action; (5) skin debridement properties. These biological functions of bromelain, a non‐toxic compound, have therapeutic values in modulating: (a) tumor growth; (b) blood coagulation; (c) inflammatory changes; (d) debridement of third degree burns; (e) enhancement of absorption of drugs. The mechanism of action of bromelain affecting these varied biological effects relates in part to its modldulation of the arachdhidonate cascade. Bromelain as a Treatment for Osteoarthritis: a Review of Clinical Studies Sarah Brien, George Lewith, Ann Walker, Stephen M. Hicks, and Dick Middleton –UK Evid Based Complement Alternat Med. 2004 December; 1(3): 251–257. ™Summ ar y of CCcalinical Triaasls Assessing Broeaomelain for Osteoarthritis ™The use of bromelain for the treatment of osteoarthritis looks promising. However, a number of methodological caveats indicate that fthfurther stditudies are warrantdted, in particu lar phase II clinical trials to identify the optimum dosage, followed by a definitive randomised placebo‐ controlled trial to confirm its efficacy in the treatment of osteoarthritis. Capsaicin

9 Cayenne pepper (also known as chili or red hot pepper) is the fruit of Capsicum annuum, a shrubby, tropical plant that can grow to a height of up to 3 feet. The fruit is technically a berry. Paprika is a milder and sweeter‐tasting fruit produced from a different variety of capsicum. 9 Although hot to the taste, actually lowers bdbody temperature by stimulating the cooling center of the hypothalamus in the brain. The ingestion of cayenne peppers by culture native to the tropics appears to help these people deal with high temperatures. 9 Cayenne has been used for thousands of years as a medicinal plant. CAPSAICIN ‐ Excerpted from: THE HEALING POWER OF HERBS By Michael T. Murray, ND Prima Health Publishing, 1995

9 Cayenne pepper exerts a number of beneficial effects on the cardiovascular system. In addition to possessing excellent antioxidant compounds, studies have shown that cayenne pepper reduces the like lihoo d of ddlieveloping athhlierosclerosis by reddiucing blood cholesterol and triglyceride levels. Cultures consuming large amounts of cayenne pepper have a much lower rate of cardiovascular disease. 9 Although people with active peptic ulcers may be bothered by “spicy” foods containing cayenne pepper, spicy foods do not cause ulcers in normal individuals. In fact, cayenne pepper exerts several beneficial effects on gastrointestinal function. 9 These preparations may offer significant benefit in a number of conditions, including pain disorders such as post‐amputation pain, post‐mastectomy pain, post‐herpetic neuralgia, diabetic neuropathy, cluster headaches, osteoarthritis, and rheumatoid arthritis. In addition, topically applied capsaicin may be useful in the treatment of psoriasis. 9 Cayenne pepper can be used liberally in the diet. Creams containing 0.025 or 0.075% capsaicin may be applied to affected areas up to 4x/day. Cayenne Pepper is generally recognized as safe (GRAS) in the United States. Topypically applied capsaicin may produce a local burning sensation’ however, this effect fades away with time and is rarely severe enough to prevent use of the cream. 27 studies are referenced. Capsaicin exhibits anti‐inflammatory property by inhibiting IkB‐ a degradation in LPS‐stimulated peritoneal macrophages. Kim Chu‐Sook; Kawada Teruo; Kim Byung‐Sam; Han In‐Seob; Choe Suck‐Young; Kurata Tadao; Yu Rina Cellular signalling 2003;15(3):299‐306. 9 Capsaicin, a major ingredient of hot pepper, is considered to exhibit an anti‐ inflammatory property. 9 In order to clarify the signalling mechanism underlying the anti‐inflammatory action of capsaicin, we investigated the effect of capsaicin on the production of inflammatory molecules in lipopolysaccharide (LPS)‐stimulated murine peritoneal macrophages. 9 The level of PGE2 was measured by EIA. The expression levels of COX‐2, iNOS, IkB‐a, and vanilloid receptor‐1 (VR‐1) were determined at the protein and mRNA levels. 9 Significant inhibition of the production of LPS‐induced PGE2 by capsaicin was observed in a dose‐dependent manner. 9 Capsaicin did not affect the COX‐2 expression at either the protein or mRNA level, but inhibited the enzyme activity of COX‐2 and the expression of the iNOS protein. Capsaicin completely blocked LPS‐induced disappearance of IkB‐ a and therefore inactivated NF‐kB. 9 These findings suggest that the anti‐inflammatory action of capsaicin may occur through a novel mechanism, not by a VR‐1 receptor‐mediated one. Both capsaicin and capsazepine may be a promising drug candidates for ameliorating inflammatory diseases and cancer. Sensory neuron‐specific actions of capsaicin: mechanisms and applications. Bevin S, Szolcsanyi J Sandoz, Institute for Medical Research, London, UK Trends Pharmacol Sci. 1990 Aug;11(8):330‐3

9 Capsaicin acts specifically on a subset of primary afferent sensory neurons to open cation‐selective ion channels, probably by interacting directly with a membrane receptor‐ion channel complex. 9 Another plant product‐‐resiniferatoxin‐‐has structural similarities to capsaicin and opens the same channels, but is up to 10,000 times as potent. 9 Capsaicin‐sensitive neurons are involved in nociception, are responsible for the neurogenic component of the inflammatory response and may also have efferent actions in the peripheral target tissues. 9 In addition to its excitatory actions, capsaicin can have subsequent antinociceptive and anti‐inflammatory effects. 9 For these reasons Stuart Bevan and János Szolcsányi argue that drugs based on capsaicin and resiniferatoxin may have important clinical uses. The capsaicin receptor: a heat‐activated ion channel in the pain pathway. Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D. Department of Cellular and Molecular Pharmacology, University of California, San Francisco. Nature. 1997 Oct 23; 389(6653):816 ‐24. 9 Capsaicin, the main pungent ingredient in 'hot' chilli peppers, elicits a sensation of burning pain by selectively activa ting sensory neurons tha t convey ifinforma tion abtbout noxious stimuli to the central nervous system. 9 We have used an expression cloning strategy based on calilcium iiflnflux to iltisolate a ftilfunctional cDNA encoding a capsaicin receptor from sensory neurons. 9 This receptor is a non‐selective cation channel that is sttlltructurally relltdated to members of the TRP ffilamily of ion channels. 9 The cloned capsaicin receptor is also activated by increases in temperature in the noxious range, suggesting that it functions as a transducer of painful thermal stimuli in vivo. More Than Spice: Capsaicin in Hot Chili Peppers Makes Tumor Cells Commit Suicide Young‐Joon Surh, Ph.D., College of Pharmacy, Seoul National University Journal of the National Cancer Institute, Vol. 94, No. 17, 1263‐1265, September 4, 2002 EDITORIAL 9 A receptor for capsaicin and other structurally related substances was iden tifie d and cldloned (1–3). This receptor, vanillo id receptor subtype 1 (VR1), forms a nonselective cation channel in the plasma membrane that mediates some of the pleiotropic effects exerted by capsaicin and its analogg,ues, which are collectively named vanilloids. 9 Interestingly, capsaicin has been found to preferentially repress the growth of some transformed human and mouse cells (9,10). Although the antiproliferative activity of capsaicin has been ascribe d to its ability to idinduce apoptitosis (9–18), reltillatively little is known about the molecular basis for the programmed cell death induced by this edible phytochemical. 9 We have shown that topical application of capsaicin onto the dorsal skin of mice strongly suppresses epidermal NF‐B activation induced by phorbol ester (30), which may account for the anti‐inflammatory and antitumor promoting effects of this compound. CURCUMIN

A perennial herb, the yellow‐pigment substance and component of turmeric, (Curcuma ll)onga) of the ginger fflamily that is extensively cultivated in India, China, Indonesia, and other tropical countries. It has a thick rhizome from which arise large, oblong, long‐petioled leaves. The rhizome is the part used; it is usually cured (boiled, cleaned, and sun‐dried) and polished. Turmeric is the major ingredient of curry powder and is also used in prepared mustard. It is extensively used in foods both for its color and flavor. CURCUMIN ‐ Excerpted from: THE HEALING POWER OF HERBS By Michael T. Murray, ND Prima Health Publishing, 1995

• Curcumin is as effective as cortisone or phenylbutazone in models of acute inflammation, but only half as effective in chronic models. • Curcumin displays virtually no toxicity. Curcuma longa has been used in Ayurvedic medicine, both locally and internally, in the treatment of sprains and inflammation. This use seems to be substantiated not only by experimental studies, but also by clinical investigations. • The results of these studies indicate that turmeric or curcumin may provide benefit in the treatment of inflammation. • Dosage: Turmeric should be consumed liberally in the diet. Curcumin recommended dosage is 400‐600 milligrams 3x day. Because absorption in the GI tract may be limited, curcumin is often formulated with bromelain. • You can get this in a supplement or by eating a lot of curry dishes. However, 8,000‐ 60,000 of turmeric 3x day would be required to get a similar amount of curcumin in the form of turmeric. • Toxicity: reactions have not been reported at standard dosages. The safety and excellent tolerability of curcumin compared to standard drug treatment are major advantages. GI irritation at high dosages may result because doses of 100 mg per kilogram body weight, was ulcerogenic in rats. • 44 studies are referenced in this book. Potential Therapeutic Effects of Curcumin, the Anti‐inflammatory Agent, Against Neurodeg,generative, Cardiovascular, Pulmonary, Metabolic, Autoimmune and Neoplastic Diseases Bharat B. Aggarwal and Kuzhuvelil B. Harikumar Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas Int J Biochem Cell Biol. Author manuscript; available in PMC 2010 January 1. • For centuries it has been known that turmeric exhibits anti‐inflammatory activity, but extensive research performed within the past two decades has shown that the this activity of turmeric is due to curcumin, a diferuloylmethane. • This agent has been shown to regulate numerous transcription factors, cytokines, protein kinases, adhesion molecules, redox status and enzymes that have been linked to inflammation. • The process of inflammation has been shown to play a major role in most chronic illnesses, including neurodegenerative, cardiovascular, pulmonary, metabolic, autoimmune and neoplastic diseases. • In the current review, we provide evidence for the potential role of curcumin in the prevention and treatment of various pro‐inflammatory chronic diseases. • These features, combined with the pharmacological safety and negligible cost, render curcumin an attractive agent to explore further. Efficacy and safety of Curcuma domestica extracts in patients with knee osteoarthritis. Kuptniratsaiklkul V, Thkhhanakhumtorn S, Chklhinswangwatanakul P, Wattanamongklkonsil L, Thlkklhamlikitkul V Department of Rehabilitation Medicine, Bangkok, Thailand J Altern Complement Med. 2009 Aug;15(8):891‐7. • The objective of this study was to determine the efficacy and safety of Curcuma domestica extracts in pain reduction and functional improvement in patients with knee osteoarthritis. • STUDY DESIGN AND SETTING: The design and setting were a randomized controlled study at a university hospital in Bangkok, Thailand. • METHODS: One‐hddhundred and seven (107) patients wiihth primary knee osteoarthhiiritis (OA) wihith pain score of > or =5 were randomized to receive ibuprofen 800 mg per day or C. domestica extracts 2 g per day for 6 weeks. The main outcomes were improvement in pain on level walking, pain on stairs, and functions of knee assessed by time spent during 100‐m walk and going up and down a flig ht of stairs. The adverse events were also recorddded. • RESULTS: Fifty‐two (52) and 55 patients were randomized to C. domestica extracts and ibuprofen groups, respectively. Baseline characteristics of the patients in both groups were not different. The mean scores of the aforementioned outcomes at weeks 0, 2, 4, and 6 were significantly improved when compared with the baseline values in both groups. There was no difference in those parameters between the patients receiving ibuprofen and C. domestica extracts, except pain on stairs (p = 0.016). No significant difference of adverse events between both groups was found (33.3% versus 44.2%, p = 0.36 in C. domestica extracts and ibuprofen groups, respectively). • CONCLUSIONS: C. domestica extracts seem to be similarly efficacious and safe as ibuprofen for the treatment of knee OA. Curcumin: the Indian solid gold. Aggarwal BB, Sundaram C, Malani N, Ichikawa H. Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA. Adv Exp Med Biol. 2007;595:1‐75.

Abstract: Turmeric, derived from the plant Curcuma longa, is a gold‐colored spice commonly used in the Indian subcontinent, not only for health care but also for the preservation of food and as a yellow dye for textiles. Curcumin, which gives the yellow color to turmeric, was first isolated almost two centuries ago, and its structure as diferuloylmethane was determined in 1910. Since the time of Ayurveda (1900 BCE) numerous thiherapeutic actiiiivities have been assiidgned to turmeric for a wide variety of diseases and conditions, including those of the skin, pulmonary, and gastrointestinal systems, aches, pains, wounds, sprains, and liver disorders. Extensive research within the last half century has proven that most of these activities, once associated with turmeric, are due to curcumin. Curcumin has been shown to exhibit antioxidant, anti‐ inflammatory, antiviral, antibacterial, antifungal, and anticancer activities and thus has a potential against various malignant diseases, diabetes, allergies, arthritis, Alzheimer's disease, and other chronic illnesses. These effects are mediated through the regulation of various transcription factors, growth factors, inflammatory cytokines, protein kinases, and other enzymes. Curcumin exhibits activities similar to recently discovered tumor necrosis factor blockers (e.g., HUMIRA, REMICADE, and ENBREL), a vascular endothelial cell growth factor blocker (e.g., AVASTIN), human epidermal growth factor receptor blockers (e.g., ERBITUX, ERLOTINIB, and GEFTINIB), and a HER2 blocker (e.g., HERCEPTIN). Protective effect of curcumin on oleic‐induced acute lung injury in rats [Article in Chinese] Zhu RF, Zhou M, He JL, Ding FY, Yu SQ, Xu GL. Jiangsu Key Laboratory for Supramolecular Medicinal Materials and Applications, Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, China. Zhongguo Zhong Yao Za Zhi. 2008 Sep;33(17):2141‐5. • Abstract: To investigate the effect of curcumine on acute lung injury induced by oleic acid in rat and the possible mechhianism of action. The rats were div ide d into 6 groups randldomly: normal group, control group, curcumine groups (5, 10, 20 mg x kg(‐1)) and dexamethasone group (1 mg x kg(‐1)). During the experiment, acute lung injury was induced by oleic acid in rat. The changes of dynamic lung compliance were recorded by anrise 2005 pulmonary function test apparatus, light microscope was used to examine his to log ica l changes and lung iidndex as well as wet to dry weihtight ratio was calculated by weighting method. Lung vascular permeability and protein level in BALF were detected by ultraviolet spectrophotometry, and the concentrations of TNF‐alpha, IL‐6 and IL‐10 in BALF were measured by enzyme linked immunosorbent assay (ELISA). The result showed tha t the changes of pulmonary compliance were in hibite d and pulmonary fftiunction was iidmproved by curcumine. The OA‐induced elevation of lung index was restrained, as well as wet to dry weight ratio, lung vascular permeability, protein level, TNF‐alpha (250.4 +/‐ 21.6 vs. 172.53 +/‐ 14.88, 122.2 +/‐ 10.98, 108.69 +/‐ 3.39) ng x L(‐1), IL‐6 (763.6 +/‐ 88.33 vs. 207.41 +/‐ 15.55, 172.13 +/‐ 21.91 , 142.92 +/‐ 4.32) ng x L(‐1) in BALF in curcumine groups, IL‐10 (98. 90 +/‐ 2992.99 vs. 208.44 +/‐ 16.30, 218.43 +/‐ 6.23, 252.70 +/‐ 20.58) ng x L(‐1) in BALF was increased, respectively significantly. Light microscope findings shown that the impairment in curcumine groups was far less severe than that in model groups. Pretreatment of curcumine showed beneficial effect on acute lung iijnjury idinduce d by olileic acid in rats. The media tion of bthboth proiflinflamma tory ftfactor and anti‐inflammatory factor by curcumine may be involved in mechanism of action of curcumine effects. Curcumin decreases toll‐like receptor‐2 gene expression and function in human monocytes and neutrophils. Shuto T, Ono T, Ohira Y, Shimasaki S, Mizunoe S, Watanabe K, Suico MA, Koga T, Sato T, Morino S, Sato K, Kai H. Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Global COE "Cell Fate Regulation Research and Education Unit", Kumamoto University, Japan. Biochem Biophys Res Commun. 2010 Jul 3. [Epub ahead of print] Toll‐like receptor‐2 (TLR2) is a pattern recognition receptor that senses many types of bacterial components and activates signaling pathways that induce inflammatory cytokines. A hyperresponsiveness to pathogens caused by increased expression of TLR2 triggers exaggeration of some inflammatory diseases. Here, we showed that curcumin, a well‐known anti‐inflammatory agent derived from the curry spice turmeric, inhibits TLR2 expression in various TLR2‐expressing innate immune cell lines such as monocytic THP‐1 cells, neutrophilic‐differentiated HL‐60 cells. Strong suppression of TLR2 gene expression was specifically observed at concentrations of curcumin in the range 40‐100muM. Consistent with decreased expression of TLR2 mRNA, protein expression and ligand‐ responsiveness of TLR2 were markedly reduced by curcumin treatment. Moreover, curcumin‐dependent down‐regulation of TLR2 expression and function was also observed in primary peripheral blood monocytes (MC) and polymorphonuclear neutrophils (PMN). Finally, we determined the importance of curcumin‐dependent radical generation for the suppressive effect of curcumin on TLR2 expression. Thus, our data demonstrate that curcumin inhibits TLR2 gene expression and function possibly via an oxidative process. Naturopathy

The artis t lkdlooked throug h stdtuden t's eyes At the textbook neutrophil Under the dark spectrum microscope White blood cell phagocyte Destroys micro‐organisms Gets rid of debris She saw one of these cell‐eaters Migrate over and caress a damaged cell Until it was healed. The caress told the artist's eyes They were beholding A unit of consciousness

‐‐Harlow S. Clark Dedicated to Linda Curley Christensen Synergistic chondroprotective effects of curcumin and resveratrol in human articular chondrocytes: inhibition of IL‐1β‐induced NF‐κB‐mediated inflammation and apoptosis Constanze Csaki, Ali Mobasheri and Mehdi Shakibaei Musculoskeletal Research Group, Ludwig‐Maximilians‐University Munich, Germany & Musculoskeletal Research Group, Division of Veterinary Medicine, University of Nottingham Arthiihritis Research & Therapy 2009, 11:R 165 do i: 10. 1186/ar28 50 • Currently available treatments for osteoarthritis (OA) are restricted to nonsteroidal anti‐inflammatory drugs, which exhibit numerous side effects and are only temporarily effective. Thus novel, safe and more efficacious anti‐inflammatory agents are needed for OA. Naturally occurring polyphenolic compounds, such as curcumin and resveratrol, are potent agents for modulating inflammation. Both compounds mediate their effects by targeting the NF‐κB signalling pathway. • We have recently demonstrated that in chondrocytes resveratrol modulates the NF‐κB pathway by inhibiting the proteasome, while curcumin modulates the activation of NF‐κB by inhibiting upstream kinases (Akt). • The aim of this study was to investigate the potential synergistic effects of curcumin and resveratrol on IL‐1β‐stimulated human chondrocytes in vitro using immunoblotting and electron microscopy. Arthritis Research & Therapy 2009, 11:R165doi:10.1186/ar2850 continued Synergistic chondroprotective effects of curcumin and resveratrol in human articular chondrocytes:

• Results: Treatment with curcumin and resveratrol suppressed NF‐ κB‐regulated gene products involved in inflammation (cyclooxygenase‐2, matrix metalloproteinase (MMP)‐3, MMP‐9, vascular endothelial growth factor), inhibited apoptosis (Bcl‐2, Bcl‐ xL, and TNF‐α receptor‐associated factor 1) and prevented activation of caspase‐3. • IL‐1β‐induced NF‐κB activation was suppressed directly by cocktails of curcumin and resveratrol through inhibition of Iκκ and proteasome activation, inhibition of IκBα phosphorylation and degradation, and inhibition of nuclear translocation of NF‐κB. The modulatory effects of curcumin and resveratrol on IL‐1β‐induced expression of cartilage specific matrix and proinflammatory enzymes were mediated in part by the cartilage‐specific transcription factor Sox‐9. • Conclusions: We propose that combining these natural compounds may be a useful strategy in OA therapy as compared with separate treatment with each individual compound. Biological actions of curcumin on articular chondrocytes. Henrotin Y, Clutterbuck AL, Allaway D, Lodwig EM, Harris P, Mathy‐Hartert M, Shakibaei M, Mobasheri A. UiUnivers ity of Liège, ItittInstitute of PthlPathology, StSart‐Tilman, Liège, BliBelgium. Osteoarthritis Cartilage. 2010 Feb;18(2):141‐9. Epub 2009 Oct 8.

• Recent work has shown that curcumin protects human chondrocytes from the catabolic actions of interleukin‐1 beta (IL‐1beta) including matrix metalloproteinase (MMP)‐3 up‐regulation, inhibition of collagen type II and down‐regulation of beta1‐integrin expression. • Curcumin blocks IL‐1beta‐induced proteoglycan degradation, AP‐1/NF‐ kappaB signalling, chdhondrocyte apoptosis and activation of caspase‐3. • Curcumin blocks IL‐1beta‐induced proteoglycan degradation, AP‐1/NF‐ kappaB signalling, chondrocyte apoptosis and activation of caspase‐3. • The available data from published in vitro and in vivo studies suggest that curcumin may be a beneficial complementary treatment for OA in humans and companion animals. • Nevertheless, before initiating extensive clinical trials, more basic research is required to improve its solubility, absorption and bioavailability and gain additional information about its safety and efficacy in different species. • Once these obstacles have been overcome, curcumin and structurally related biochemicals may become safer and more suitable nutraceutical alilternatives to the non‐steroida l anti‐iflinflammatory drugs that are currently used for the treatment of OA. GINGER

Ginger is a perennial herb with thkhick tuberous rhizomes. Wild ginger grows 2‐4 feet high and produces a beautiful flower. It is native to southern Asia but Jamaica is the major pp,roducer, with exports to all parts of the world. The knotted and branched rhizome, commonly called the “”“root,” is the portion of ginger used for culinary and medicinal purposes. GINGER Excerpted from: THE HEALING POWER OF HERBS By Michael T. Murray, ND Prima Health Publishing, 1995

• Ginger’s ability to inhibit the formation of inflammatory prostaglandins, thromboxanes, and leukotrienes, along with its strong antioxidant activities, suggest a possible benefit in inflammatory conditions. • Ginger has been used for thousands of years in China for medicinal purposes. It was used to treat stomachache, diarrhea, nausea, cholera, hemorrhage, rheumatism, and toothaches. Historically, ginger is known for its use as an anti‐ inflammatory agent. It also helps lower cholesterol and has demonstrated analgesic effects in experimental studies. Ginger demonstrates significant anti‐ ulcer effects and is noted for its apparent ability to warm the body. • Dosage: Recommended dose for inflammatory conditions such as rheumatoid arthritis is 2 to 4 grams of dry powdered ginger per day. The equivalent of fresh ginger root is 20 grams, 2/3 ounce or roughly a ½ inch slice. • Toxicity: Ginger does not appear to be toxic and the recommended dose. Administration of 6 grams of dried powdered ginger alone on an empty stomach may cause some GI distress. • This information was taken from 43 studies and references listed in the book. Ginger‐‐an herbal medicinal product with broad anti‐ inflammatory actions. Grzanna R, Lin dmar k L, FdFrondoza CG. J Med Food. 2005 Summer;8(2):125‐32. • The original discovery of ginger's inhibitory effects on prostaglandin biosynthesis in the early 1970s has been reppyeatedly confirmed. This discovery identified ggginger as an herbal medicinal product that shares pharmacological properties with non‐steroidal anti‐inflammatory drugs. • Ginger suppresses prostaglandin synthesis through inhibition of cyclooxygenase‐1 and cyclooxygenase‐2. • Ginger also suppresses leukotriene biosynthesis by inhibiting 5‐lipoxygenase. This pharmacological property distinguishes ginger from nonsteroidal anti‐inflammatory drugs. This discovery preceded the observation that dual inhibitors of cyclooxygenase and 5‐lipoxygenase may have a better therapeutic profile and have fewer side effects than non‐steroidal anti‐ inflammatory drugs • Ginger extract (EV.EXT.77) derived from Zingiber officinale (family Zingiberaceae) and Alpina galanga (family Zingiberaceae) inhibits the induction of several genes involved in the inflammatory response. These include genes encoding cytokines, chemokines, and the inducible enzyme cyclooxygenase‐2. • This discovery provided the first evidence that ginger modulates biochemical pathways activated in chronic inflammation. • Identification of the molecular targets of individual ginger constituents provides an opportunity to optimize and standardize ginger products with respect to their effects on specific biomarkers of inflammation. Such preparations will be useful for studies in experimental animals and humans. Condor Woods The Canyons Ski Resort, Park City, UT BOSWELIA ‐ FRANKINCENSE

• Also known as olibanum, is the resin from the trees of the genus Boswellia native to Arabia and India. It has a long history of use. • Both myrrh and frankincense grow as small trees or shrubs; they are of the botanical family Burseraceae. Frankincense in the Dhofar region of Oman. Frankincense: systematic review E Ernst, BMJ. 2008; 337: a2813 PblihdPublished online 2008 Dec. 17 Complementary Medicine, Peninsula Medical School, Universities of Exeter and Plymouth, Exeter, UK • Seven randomised clinical trials were included, studies were published between 1998 and 2008 and most came from India. Methodological quality was variable but three trials reached the maximum on the Jadad scale.10 11 13 Five trials were placebo controlled and two were comparisons against active treatments. All studies used oral administration of B serrata extracts. • Boswellia extracts showed some promise in treating asthma,7 rheumatoid arthritis,8 Crohn’s disease,9 knee osteoarthritis,10 12 13 and collagenous colit is.11 However, all the iilddncluded triilals hhdad flaws: the most common limitations were small sample size and incomplete reporting of data. • The evidence evaluated here may be encouraging, but it is not convincing. Not enough large randdidomised clin ica l triilals have been publis he d for any condition. The medications used in these trials cannot be directly compared in terms of contents and strength. The pharmacokinetics and optimal dose of B serrata extracts are largely unknown; usually 600‐3000 mg gum resin per day or equivalents are recommended for oral intake.1 Boswellia–Curcumin Preparation for Treating Knee Osteoarthritis: A Clinical Evaluation Farid A. Badria, Ph.D., Tamer El‐Farahaty, M.Sc., Adel A. Shabana, M.D., Samia A. Hawas, M.D., and M. Fathy El‐Batoty, M.D. Alternative & Complementary Therapies , Volume 8 (6) Mary Ann Liebert –Dec 1, 2002

• OA has been considered to be a degenerative joint disease. However, the dominant clinical manifestations have been characterized by a chronic inflammatory process in which chondrocytes degenerate and/or osteophytes form. • Among patient s with OA, levels of CD4 in synovial fluid and sera have been found to be higher than those in sera of healthy individuals. • Immune response in primary OA has been extensively examined. Immunohistochemical staining of synovial tissue of OA joints in the early stage has indicated T‐cell infiltration in the perivascular area and some of the cell s were CD4+ T‐cells. 2 Reactive oxygen species (ROS) are implicated in cartilage aging and OA pathogenesis. • Synoviocytes and chondrocytes produce nitric oxide (NO), which produces highly toxic peroxynitrite. • NO is also capable of inducing apoptosis in chrondrocytes. • Superoxide dismutase (SOD) enzyme is an important defensive antioxidant. It is known to dismutate the superoxide anion radical. Very low levels of circulating SOD have been observed in inflammatory arthritis; Boswellia–Curcumin Preparation for Treating Knee Osteoarthritis: A Clinical Evaluation ‐ continued • The purpose of this study was to evaluate the efficacy of a boswellia ‐ curcumin preparation for managing knee OA. • The preparation consisted of extracts of Boswellia carteri (olibanum; 37.5 percent boswellic acid) and turmeric in 500‐mg hard gelatin capsules. • Both clinical (nocturnal pain, pain on walking, pain produced by passive movements, tenderness, effusion, and painfree walking time) and laboratory (SOD, NO, and T‐cell receptors) parameters were used throughout the 3‐ month study, which was a double‐blinded, randomized crossover trial. • Subjects were selected from the outpatient clinic of the department of rheumatology and rehabilitation of Mansoura University Hospital, Mansoura, Egypt. GUGULIPID – MYRRH Excerpted from: THE HEALING POWER OF HERBS By Michael T. Murray, ND Prima Health Publishing, 1995 • Gugulipid is derived from the mukul myrrh tree native (Commiphora mukul) to Arabia and India. The tree exudes a yellowish gum resin referred to as “gum guggul” or “guggulu.” This resin is used for medicinal purposes and is a highly valued botanical medicine in the Indian system of medicine, Ayurveda. • This medicinal plant exhibits significant anti‐inflammatory action in experimental models of inflammation. • Dosage: 25‐50 milligrams of guggulsterone 3x day ((llusually ffdound as a sttddidandardized extract of the gum guggul) is common. • Toxicity: Used in the standard for of extract , it is virtually nontoxic. The crude gum guggul is not preferred as it has non‐ pharmacological toxic components. New triterpenes, myrrhanol A and myrrhanone A, from guggul‐gum resins, and their potent anti‐inflammatory effect on adjuvant‐ induced air‐pouch granuloma of mice Ikuko Kimura, Masayuki Yoshikawa, Shinjiro Kobayashi, Japan Bioorganic & Medicinal Chemistry Letters Volume 11, Issue 8, 23 April 2001, Pages 985‐989 • Abstract: Myrrhanol A, a new triterpene isolated from guggul (Balsamodendron or Commiphora mukul Hook.)‐ gum resin, displays a potent anti‐inflammatory effect on exudtidative pouch fluid , angiiiogenesis, and granuloma weights in adjuvant‐induced air‐pouch granuloma of mice. Its effects were more marked than those of hydrocortisone and the 50% aqueous methanolic extract of the crude drug. Myrrhanol A is a plausible candidate for a potent anti‐ inflammatory agent. • Myrrhanol A, a new triterpene isolated from guggul (Balsamodendron mukul Hook.)‐gum resin, displays a potent anti‐inflammatory effect on exudative pouch fluid, angiogenesis, and granuloma weights in adjuvant‐induced air‐pouch granuloma of mice. Anti‐inflammatory studies on a crystalline steroid isolated from Commiphora mklmukul. Arora RB, Taneja V, Sharma RC, et al. Indian J Med Res 1972; 60(6):929‐931.

• Anti‐inflammatory properties were reported. • This work has been cited by many other studies. Guggulsterone blocks IL‐1β‐mediated inflammatory responses by suppressing NF‐κB activation in fibroblast‐like synoviocytes Young‐Rae Lee, Ji‐Hyun Lee, et. al. Republic of Korea Life Sciences Volume 82, Issues 23‐24, 6 June 2008, Pages 1203‐1209 • Abstract: Guggulsterone is a plant sterol that is used to treat hyperlipidemia, arthritis, and obesity. Although its anti‐inflammatory and anti‐hyperlipidemic effects have been well documented, the effect of guggulsterone on fibroblast‐like synoviocytes (FLS) has not yet been reported. Therefore, in this study, the effect of guggulsterone on interleukin (IL)‐1β‐induced inflammatory responses in the FLS of rheumatic patients was investigated. Treatment of FLS with IL‐1β induced production of chemokines such as RANTES and ENA‐78. In addition, Western blot analysis and gelatin zymography revealed that IL‐1β activated matrix metalloproteinase (MMP)‐1 and ‐3 in FLS. However, pre‐ incubation with guggulsterone completely inhibited the ability of IL‐1β to induce the production of chemokines and to activate MMPs. Although the NF‐κB binding activity and nuclear p50 and p65 subunit levels, as well as IκBα degradation in the cytoplasm was greater in cells stimulated with IL‐ 1β than in unstimulated cells, treatment with guggulsterone abolished all of these increases. • Collectively, these results suggest that guggulsterone would be useful as an ihibiinhibitor of jijoint didestruction in patients wihith rhidheumatoid arthiihritis. Guggulsterone Inhibits NF‐κB and IκBα Kinase Activation, Suppresses Expression of Anti‐apoptotic Gene Products, and Enhances Apoptosis Shishir Shishodia, Bharat B. Aggarwal, A Ransom Horne Jr., University of Texas M. D. Anderson Cancer Center November 5, 2004 The Journal of Biological Chemistry, 279, 47148‐47158.

• Abstract: Guggulsterone, derived from Commiphora mukul and used to treat obesity, diabetes, hyperlipidemia, atherosclerosis, and osteoarthritis, has been recently shown to antagonize the farnesoid X receptor and decrease the expression of bile acid‐ activated genes. Because activation of NF‐κB has been closely linked with inflammatory diseases affected by guggulsterone, we postulated that it must modulate NF‐κB activation. In the present study, we tested this hypothesis by investigggating the effect of this steroid on the activation of NF‐κB induced by inflammatory agents and carcinogens. Guggulsterone suppressed DNA binding of NF‐κB induced by tumor necrosis factor (TNF), phorbol ester, okadaic acid, cigarette smoke condensate, hydrogen peroxide, and interleukin‐1. NF‐κB activation was not cell type‐specific, because both epithelial and leukemia cells were inhibited. Guggulsterone also suppressed constitutive NF‐κB activation expressed in most tumor cells. Through inhibition of IκB kinase activation, this steroid blocked IκBα phosphorylation and degradation, thus suppressing p65 phosphorylation and nuclear translocation. NF‐κB‐ dependent reporter gene transcription induced by TNF, TNFR1, TRADD, TRAF2, NIK, and IKK was also blocked by guggulsterone but without affecting p65‐mediated gene transcription. In addition, guggulsterone decreased the expression of gene products involved in anti‐apoptosis (IAP1, xIAP, Bfl‐1/A1, Bcl‐2, cFLIP, and survivin), proliferation (cyclin D1 and c‐Myc), and metastasis (MMP‐9, COX‐2, and VEGF); this correlated with enhancement of apoptosis induced by TNF and chemotherapeutic agents. • Overall, our results indicate that guggulsterone suppresses NF‐κB and NF‐κB‐regulated gene products, which may explain its anti‐inflammatory activities. Suppression of the nuclear factor‐kappaB activation pathway by spice‐ derived phytochemicals: reasoning for seasoning. B Aggarwal Shhdhishodia S Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas BAnn N Y Acad Sci. 2004 Dec;1030:434‐41.

Abstract: The activation of nuclear transcription factor kappaB has now been linked with a variety of inflammatory diseases, including cancer, atherosclerosis, myocardial infarction, diabetes, allergy, asthma, arthritis, Crohn's disease, multiple sclerosis, Alzheimer's disease, osteoporosis, psoriasis, septic shock, and AIDS. Extensive research in the last few years has shown that the pathway that activates this transcription factor can be interrupted by phytochemicals derived from spices such as turmeric (curcumin), red pepper (capsaicin), cloves (eugenol), ginger (gingerol), cumin, anise, and fennel (anethol), basil and rosemary (ursolic acid), garlic (dia lly l sulfide, S‐ally lmercaptocyste ine, aj)joene), and pomegranate (ellagic acid). For the first time, therefore, research provides "reasoning for seasoning." Natural Antiinflammatory Agents for Pain Relief in Athletes Joseph C. Maroon, M.D.; Jeffrey W. Bost, P. A .‐C.; Meghan K. Borden; Keith M. Lorenz; Nathan A. Ross Neurosurg Focus. 2006;21(4) © 2006 American Association of Neurological Surgeons • Abstract Most athletes experience musculoskeletal injuries during their sports activity that require rest at a minimum, and occasionally injuries are severe enough to necessitate surgical repair. Neurosurgeons are often consulted for athle tica lly sustitaine d iijnjur ies and prescribe medica tions for the associated pain. The use of both over‐the‐counter and prescription nonsteroidal medications is frequently recommended, but recent safety concerns must now be considered. The authors discuss the biochemical pathways of nonsteroidal drugs and review the potentially serious side effects of these medications. They also review the use of natural supplements, which may be a safer, and often as effective, alternative treatment for pain relief. Corydalis yanhusuo Tuber

• Corydalis is the name of a group of herbs used in different parts of the world to relieve pain . Corydalis yanhusuo is a species used primarily in Chinese herbal medicine. In traditional Chinese medicine (TCM), C. yanhusuo is said to have a warm nature and a pungent, bitter taste. It is associated with the heart, liver, and spleen. C. yanhusuo is used to relieve pain resulting from almost any cause. It is especially used to treat menstrual cramps, chest pains, and abdominal pain. Corydalis is also the preferred herb in treating pain from traumatic injuries. Some herbalists report that frying corydalis in vinegar enhances its ability to ease pain. Anti‐inflammatory activities of methanolic extract and alkaloidal components from Corydalis tuber. Kubo M, Matsuda H, Tokuoka K, Ma S, Shiomoto H. Faculty of Pharmaceutical Sciences, Kinki University, Osaka, Japan. Biol Pharm Bull. 1994 Feb;17(2):262‐5

• A methanolic extract (CM‐ext) from Corydalis tuber (Corydalis turtschaninovii Besser forma yanhusuo Y. H. Chou et C. C. Hsu) has been screened for activity in experimental models of inflammation. • CM‐ext (200 or 500 mg/kg, p.o.) inhibited an increase in vascular permeability in mice induced by acetic acid, and reduced acute paw edema in rats induced by compound 48/80 or carrageenin. • CM‐etext su ppressed the dev elopment of adjuv ant‐induced edema in arthritic rats. CM‐ext and its alkaloidal components, dehydrocorydaline, d‐glaucine and l‐tetrahydrocoptisine inhibited compound 48/80‐induced histamine release from peritoneal mast cells of rats. • Since these substances from C. tuber were found to be effective in both the acute and chronic phases of inflammation, the crude drug C. tuber can be considered to exert anti‐inflammatory activity. Quaternary alkaloid, pseudocoptisine isolated from tubers of Corydalis turtschaninovi inhibits LPS‐induced nitric oxide, PGE(2), and pro‐ iflinflammat ory cyttkiokines proddtiuction via the down‐regultilation of NF‐kBkappaB in RAW 264.7 murine macrophage cells. Yun KJ, Shin JS, Choi JH, Back NI, Chung HG, Lee KT. , College of Pharmacy, Kyung‐Hee Univ. Int Immunopharmacol. 2009 Oct;;(9(11) :1323‐31. It is well known that pro‐inflammatory mediators like nitric oxide (NO), prostaglandin E(2) (PGE(2)), tumor necrosis factor‐alpha (TNF‐alpha), and interleukin‐6 (IL‐6) contribute to the courses of many inflammatory diseases. In the present study, the authors investigated the anti‐inflammatory effects of pseudocoptisine, a quaternary alkaloid with a benzylisoquinoline skeleton, which was isolated from the tubers of Corydalis turtschaninovii by examining its inhibitory effects on pro‐ inflammatory mediators in lipopolysaccharide (LPS)‐stimulated murine macrophage RAW 264.7 cells. Pseudocoptisine caused dose‐dependent reductions in the levels of inducible nitric oxide (iNOS) and cyclooxygenase‐2 (COX‐2) at both protein and mRNA levels and concomitant decreases in PGE(2) and NO production. In addition, it was found that pseudocoptisine suppressed the production and mRNA expressions of inflammatory cytokines, such as, TNF‐alpha and IL‐6. Furthermore, molecular data revealed that pseudocoptisine inhibited the LPS‐stimulated DNA binding activity and the transcription activity of nuclear factor‐kappa B (NF‐kappaB). Moreover, this effect was accompanied by decreases in the phosphorylation of inhibitory kappaB (IkappaB)‐ alpha and in the subsequent blocking of p65 subunit of NF‐kappaB translocation to the nucleus. In addition, pseudocoptisine dose‐dependently inhibited the phosphorylations of ERK and p38. Taken together, these results suggest that pseudocoptisine reduces levels of the pro‐inflammatory mediators, such as, iNOS, COX‐2, TNF‐alpha, and IL‐6 through the inhibition of NF‐kappaB activation via the suppression of ERK and p38 phosphorylation in RAW 264.7 cells. These findings reveal in part the molecular basis for the anti‐inflammatory properties of pseudocoptisine. Effects of Corydalis yanhusuo and Angelicae dahuricae on cold pressor‐induced pain in humans: a controlled trial. Tang Center for Herblbal Medicine Research, Committee on Clllinical Phhlarmacology, and Department of Anesthesia & Critical Care, Pritzker School of Medicine, University of Chicago, Illinois J Clin Pharmacol. 2004 Nov;;()44(11):1323‐7. • In this controlled clinical trial, the authors evaluated the analgesic effects of 2 herbal medicines, Corydalis yanhusuo and Angelicae dahuricae. They used the cold‐pressor test‐a simple, reliable, and widely used model in humans‐for induction of tonic pain. They demonstrated that after a silingle, oral addiittiministration of the extttracts of Cory da lils yanhusuo and A. dahuricae, the pain intensity and pain bothersomeness scores significantly decreased . Dose‐ related analgesic effect was also observed. Results from this study suggest that Corydalis yanhusuo and A. dahuricae may have a potential clinical value for treating mild to moderate pain. Anti‐inflammatory effect of Columbianetin on activated human mast cells. Jeong HJ, Na HJ, Kim SJ, Rim HK, Myung NY, Moon PD, Han NR, Seo JU, Kang TH, Kim JJ, et.al. Biochi p RhResearch CtCenter, Hoseo UiUnivers ity, Chungnam, RRbliepublic of Korea. Biol Pharm Bull. 2009 Jun;32(6):1027‐31 • In the present study, we extracted Corydalis heterocarpa with various solvents in order to find the bioactive constituents that demonstrated anti‐inflammatory effects. We isolated the active compound, Columbianetin. Anti‐inflammatory effect of Columbianetin has been reported but the precise effects of Columbianetin in experimental models have remained unknown. In the present study, we investigate the effect of Columbianetin on the production of histamine, interleukin (()IL)‐1beta, IL‐6, IL‐8, and tumor necrosis factor (TNF)‐alpha and expression of cyclooxygenase‐2 (COX‐2) by using the human mast cell line (HMC‐1). Various concentrations of Columbianetin were treated before the activation of HMC‐1 cells with phorbol 12‐myristate 13‐acetate (PMA) plus calcium ionophore, A23187. PMA plus A23187 significantly increased IL‐ 1beta, IL‐6, IL‐8, and TNF‐alpha production compared with media control (p<0. 05). We also show that the increased cytokines IL‐1beta, IL‐6, IL‐8, and TNF‐alpha level was significantly inhibited by Columbianetin in a dose‐dependent manner (p<0.05). Maximal inhibition rates of IL‐1beta, IL‐6, IL‐8, and TNF‐alpha production by Columbianetin were about 102.6%, 101.1%, 95.8%, and 103.9%, respypectively. Columbianetin inhibited expression of COX‐2. In addition, the effect of Columbianetin was investigated on the histamine release from HMC‐1 stimulated by substance P, which promotes histamine release. Columbianetin also inhibited the histamine release by substance P. In conclusion, these results indicate that Columbianetin may be helpful in regulating mast cell‐mediated allergic inflammatory responses. Anti‐inflammatory effect of coumarins isolated from Corydalis heterocarpa in HT‐29 human colon carcinoma cells Kyong‐Hwa Kang, Chang‐Suk Kong, Youngwan Seo, Moon‐Moo Kim, Se‐Kwon Kim Authors represent three Universities in the Republic of Korea Food and Chemical Toxicology Volume 47, Issue 8, August 2009, Pages 2129‐2134

• We investigated anti‐inflammatory effects of two coumarins, columbianetin (A) and libanoridin (B), isolated from Corydalis heterocarpa in lipopolysaccharide (LPS)‐stimulated HT‐29 human colon carcinoma cells. Treatment wiihth compound B ihibidinhibited the protein expression levels of inflammatory mediators such as inducible nitric oxide synthase (iNOS), cyclooxygenase‐2 (COX‐2), tumor necrosis factor‐α (TNF‐α), and interleukin‐1β (IL‐1β) in a dose‐dependent manner in LPS‐stimulated HT‐29 cells, but compound A did not. Also, compound B had a higher inhibitory effect on production of cytokines such as IL‐1β and TNF‐α in LPS‐stimulated HT‐29 human colon carcinoma cells than those of compound A. Furthermore, we confirmed that LPS‐induced transcription activity of NF‐κB was inhibited by compound B. As a result of this study, compound B can be considered as a potential anti‐inflammatory agent. Eggshell membrane: A possible new natural therapeutic for joint and connective tissue disorders. Results from two open‐label human clinical studies KiKevin J RffRuff, DlDale P DVDeVore, Mic hae l D Leu, and MMkark A RbiRobinson Clin Interv Aging. 2009; 4: 235–240. • Natural Eggshell Membrane (NEM®) is a novel dietary supplement that contains naturally occurring glycosaminoglycans and proteins essential for maintaining healthy joint and connective tissues. Two single center, open‐label human clinical studies were conducted to evaluate the efficacy and safety of NEM® as a treatment for pain and inflexibility associated with joint and connective tissue disorders. • Eleven (single‐arm trial) and 28 (double‐arm trial) patients received oral NEM® 500 mg once daily for four weeks. • The primary outcome measure was to evaluate the change in general pain associated with the treatment joints/areas (both studies). In the single‐arm trial, range of motion (ROM) and related ROM‐associated pain was also evaluated. Both clinical assessments were performed on the intent‐to‐treat (ITT) population within each study. • Single‐arm trial: Supplementation with NEM® produced a significant treatment response at seven days for flexibility (27.8% increase; P = 0.038) and at 30 days for general pain (72.5% reduction; P = 0.007), flexibility (43.7% increase; P = 0.006), and ROM‐associated pain (75.9% reduction; P = 0.021). • Double‐arm trial: Supplementation with NEM® produced a significant treatment response for pain at seven days for both treatment arms (X: 18.4% reduction; P = 0.021. Y: 31.3% reduction; P = 0.014). • There was no clinically meaningful difference between treatment arms at seven days, so the Y arm crossed over to the X formulation for the remainder of the study. The significant treatment response continued through 30 days for pain (30. 2% reduction; P = 0.0001) . There were no adverse events reported during either study and the treatment was reported to be well tolerated by study participants. Homeopathic Preparations National Institutes of Health, National Center for Complementary and Alternative Medicine • The principle of similars (or "like cures like") states that a disease can be cured by a substance that produces similar symptoms in healthy people. This idea, which can be traced back to Hippocrates, was further developed by Hahnemann (1755‐1843). • The principle of dilutions (or "law of minimum dose") states that the lower the dose of the medication, the greater its effectiveness. In homeopathy, substances are diluted in a stepwise fashion ,"potentization," is believed to transmit some form of information or energy from the oriiigina l subbtstance to the fina l dilu te d remedy. MMtost hhthiomeopathic remedies are so dilu te tha t no molecules of the healing substance remain; it is believed that the substance has left its imprint or "essence," which stimulates the body to heal itself (this theory is called the "memory of water"). • Homeopathy has made several important indirect contributions to the practice of medicine. At the time that it was developed, the medical treatments were often more dangerous than the disease that they purported to treat. Homeopathy may have helped hasten the demise of such treatments. Homeopathy provided the initial idea and source for useful drugs such as nitroglycerin and aconite. Homeopathy has also been given credit for providing early support for clinical trials with control groups, systematic and quantitative procedures and the use of statistics in medicine. • Our current Immunization system is based on a homeopathic model, i.e. giving a dilute substance of what can cause a disease can spur the bodies systems to fight and heal the disease. (KJC) • There are challenges in studygying homeopypathy and controversies regggarding the field, largygely because a number of its key concepts are not consistent with the current understanding of science, particularly chemistry and physics. There is limited research on the safety of homeopathic treatments. Treatment of Sports Injuries with Traumeel Ointment A Controlled Double‐Blind Study Dr. D. Bohmer, M. D., and Dr. P. Ambrus, M.D. Institute of Sports Medicine at Johann Wolfgang Goethe University, Frankfurt, Germany Biological Therapy / Vol. X / No. 4 1992 • Traumeel ointment in its normal commercially available form (Traumeel S), and in a form of this preparation contaiiining only six constituents (Traumee l Sine ) and wihith a plblacebo (Traumee l ointment base). • 102 patients with sports injuries: first‐ and second‐degree sprains and contusions. were included in this study, with breakdown into groups of 34 patients each (only 1 patient dropped out). • On the average, the patients in the two Traumeel groups were able to resume athletic training sooner(12.2 days) than the patients in the placebo group (13.5 days). • The mean abatement of swelling was approximately the same for the two Traumeel groups(‐4.38 cm), and less for the placebo group (‐3.46 cm). • Skin temperature, no differences became apparent among the three treatment groups. • Maximum muscle force Traumeel compared to contralateral, non‐injured side (‐2.32), placebo group (‐7.94). • Pain Index: a cumulative index value composed of summed values for pain experienced at rest, in motion, and under pressure (each valued on a scale of O to 2: 0 = no pain; 1 = slight pain; 2 = severe pain). Traumeel groups 1.0, Placebo 1.8 • There is no difference between the effectiveness of Traumeel S and Traumeel Sine, but that the effectiveness of both differs from that of the placebo. • During the entire course of the study, no undesired side effects were observed for any of the patients in any of the three therapy groups. Mt. Timpanogos Treatment of Inflammatory Rheumatic Diseases with Traumeel H. Mihoc, M.D. Bilogical Therapy, Vol. IV, November 1986, pp. 53‐56 (Germany)

• RX: 2 x weekly parenteral infiltration with Traumeel injection solution without additional administration of synthetic non‐steroidal antiphlogistics or steroids), • Patient Evaluations: In total 53 patients, male (17) and female (36) were documented. The average age of the patients was 61.4 years. They were almost exclllusively patients with pollhyarthritis, partially in the inflammatory phase (please refer to Erythrocyte Sedimentation Rate (E. S. R.) values). • The patients stayed for approximately 30 days in the sanatorium and were given a vegetarian alkalising diet during this period. • Improvement in the complaints occurred after an average 15.3 days after commencement of treatment. No information is available on 4 patients, but in 3 of these freedom from complaints occurred after 10 or 20 days, so that only 1 case must be classified as a therapeutic failure. Out of the total of 53 patients, a total of 28 achieved complete freedom from complaints in an average period of 23.5 days. A reduction in the E.S.R. to differing extents occurred in 25 cases related to the 2‐hour value after completion of therapy. 15 of these had freedom from complaints, 9 an improvement in the symptoms. EFFECTIVENESS OF THE TREATMENT OF DEGENERATIVE JOINT DISEASE WITH PERIARTICULAR, INTRAARTICULAR, AND INTRAMUSCULAR INJECTIONS OF ZEEL T AdAndrzej LikLesiak (Warsaw) , RiRainer GldGottwald (Mann he im ), Mic hae l WiWeiser, (Ba den‐BdBaden ) Medycyna Biologiczna, April‐June 2001, No. 2, pp. 30‐36. • Effectiveness of the treatment of degenerative joint disease by Zeel ijinjec tions was assessed on the bibasis of publis he d work and our own experience, including the results of a study carried out in a group of 523 patients. • The solution was injected into the affected joints, periarticularly and intramuscularly. We also assessed the product’s tolerability. Women were predominant (71%) in the study group. • The duration of the disease varied between 1 and 10 years, with an average of 5 years. The condition was diagnosed in the knees (53%), vertebrae (30%), hips (29%), shoulders (13%), fingers (7%), tarsal joints (6%), and other joints (5%). • The first signs of regression of the symptoms were noted in approximately 2/3 of the patients already after 6 injections, and after 10 injections a considerable improvement was observed in 94% of the cases. • The results of the treatment were rated as very good, good, or satisfactory both by doctors and patients. Experimental Studies on the Anti‐Inflammatory Activity of a Homeopathic Preparation A. Conforti, S. Bertani, H. Metelmann, S. Chirumbolo, S. Lussignoli, P. Bellavite (Italy & Germany) BIOMEDICAL THERAPY, INTERNATIONAL J. OF INTEGRATED MEDICINE, Volume XV No.1 1997 pp 28‐31 • The anti‐inflammatory effects of Arnica montana, either alone or in combination with other homeopathic substances, have been observed in experimental and clinical studies. However, its mechanism of action has not been elucidated. • The effect of Traumeel S on two important cellular functions, namely superoxide anion production and human platelet adhesion, was tested. Traumeel S did not affect either of these cellular functions, suggesting that its anti‐inflammatory effects are not due to granulocycte and platelet inhibition. • These findings also suggest that the antimicrobial functions of immune cells such as granulocyctes are not disrupted by Traumeel S. • In vivo experiments using models of chronic and acute inflammation show that in the case of submaximal activation of the inflammatory response, Traumeel@S significantly reduces the development of local edema (such as that seen in the first phase of adjuvant arthritis) and causes a 15% reduction of the carrageenan‐ induced edema when administered locally. • These results suggest that the anti‐inflammatory effects of Traumeel@S are not due to its action on a specific type of immunomodulating cell or due to a biochemical mechanism associated with conventional anti‐inflammatory drugs. Instead, Traumeel@S appears to inhibit the acute inflammatory process at the local level. Incubation in Preparations as a Means of Influencing Cartilage Mechanics: A Mechanical Study L. Web, G. Froschle, Orthopedic Clinic Hamburg‐Eppendorf University, West Germany Biological Therapy, Vol. VIII, No. 4 October 1990, pp. 91‐93 • Experimental set up: Samples of cartilage from the joints of patients requiring an endoprosthetic replacement joint were examined to determine indentation hardness prior to and following incubation in a culture and a pharmaceutical. • Cylinders of cortex cartilage with a height of 1.3‐ 3.8 mm were prepared using a punch with a diameter of 7 mm. These were accurately separated into two equal quantities. • The tests were conducted using a special device for testing hardness in order to establish elastic ductility. • The samples were placed in a culture (25 ml Hank’s isotonic solution) and were incubated for 12 days following application of Zeel@, 2.2 ml. • Simultaneous cartilage incubation without any medical preparation was carried out as a placebo series. • Following completion of the incubation period, tests were conducted on the second set of samples to determine their indentation hardness. • Results: In the case of the samples incubated with Zeel@, the increase in the ddthepth of penetttiration bbtetween the firs t and second measurements averaged 18%, while penetration depth increased by an average of6% in the case of samples incubated in the culture only. Treatment of Osteoarthritis of the Knee with Zeel T Rainer Gottwald and Michael Weiser I N T E R N A T I O N A L J O U R N A L F O R B I O M E D I C A L R E S E A R C H A N D T H E R A P Y Translated from Medicina Biológica Vol. 13, No. 4, 2000, pp. 109–113 • In a drug monitoring study 100 patients were treated for ostthititeoarthritis of the knee with the hhthiomeopathic remedy ZZleel T (injection solution). • The duration of treatment ranged from 2 to 8 weeks (97% of the patients) with a maximum for a 4–6 weeks treatment (58%). • The majority of patients revealed fast improvement of the symptoms, with 76% reporting improvement after 6 injections. • The clinical symptoms were reduced significantly and in a linear manner. Correlation coefficients showed a high correlation between the number of injections and the relief in symptoms. • The general efficacy of the treatment was assessed by the iiinvestigators as ‘very good’ or ‘d’‘good’ in 70% the cases. • The tolerability assessment of Zeel T by the investigators was ‘excellent’ or ‘good’ in 92% of the cases. Side effects were reported for 2 patients, who complained about painful injection procedures. High sensitivity C‐reactive protein (hs‐CRP) C‐reactive protein (CRP) is a protein fdfound in the bloo d, the lllevels of which rise in response to inflammation (an acute‐phase protein). Its physiological role is to bind to phosphocholine expressed on the surface of dead or dying cells (and some types of bacteria) in order to activate the complement system via the C1Q complex. • CRP is synthesized by the liver in response to factors released by fat cells (adipocytes).It is a member CRP drawn from PDB 1B09 of the penttiraxin of prottieins. High sensitivity C‐reactive protein is associated with lower tibial cartilage volume but not lower patella cartilage volume in healthy women at mid‐life Fahad S Hanna, Robin J Bell, Flavia M Cicuttini, Sonia L Davison, Anita E Wluka, Susan R Davis Arthritis Research & Therapy 2008, 10:R27

Elevated serum high sensitivity C‐reactive protein (hsCRP) has been reported in established osteoarthritis (OA). The aim of this study was to determine whether serum levels of hsCRP are associated with the variation in tibial and patella cartilage volumes in women without evidence of OA. Methods: Participants were recruited from a database established from the Australian electoral roll, and were aged 40 to 67 years, were not hysterectomized and had no significant knee pain or knee injury in the last 5 years. Tibial and patella cartilage volumes were measured from magnetic resonance imaging (MRI) of each woman's dominant knee and hsCRP measured in serum. Linear regression models were used to explore the major determinants of variation in both tibial and patella cartilage volume and to assess whether serum hsCRP made an independent contribution to variation in the volumes of cartilage in the two knee compartments. Results: The mean age of the 176 participants was 52.3 ±6.6 years. Compared with a standard model for tibial cartilage volume that included bone area, age, smoking and alcohol status, the addition of an hsCRP term made an independent negative contribution to variation in tibial cartilage volume, irrespective of whether body mass index (BMI) was included in the model or not. By contttrast, using a siiilmilar approach, hCRPhsCRP did not contibttribute idindepen den tly to varitiiation in patella cartilage volume. Conclusion: In asymptomatic women aged 40 to 67 years, serum hsCRP is independently negatively associated with the volume of tibial but not patella cartilage suggesting that subclinical inflammation may pppredispose to knee cartilage loss in the tibial compartment. This should be further assessed by a longitudinal study. Biomarkers associated with clinical phenotypes of hand osteoarthritis in a large multigenerational family : the CARRIAGE family study CHEN H.‐C. ; SHAH S. ; STABLER T. V. ; LI Y.‐J. ; KRAUS V. B. ; Osteoarthritis and Cartilage 2008, vol. 16, no9, pp. 1054‐1059

Objective: To evaluate biological markers as potential quantitative traits of clinical osteoarthritis (OA) in a large mullitigenerat iona l ffilamily in the CCliarolinas of the USA known as the CARRIAGE (Caro linas Region Interaction of Aging, Genes and Environment) family. Methods: During a series of three family reunions over 6 years, we ascertained 365 family members. We performed clinical hand examinations (n = 287), and obtained sera (n = 278) for seven OA‐ related biomarkers [type IIA collagen N‐propeptide (PIIANP), type II procollagen carboxy‐

propeptide (CPll), neoepitope from cleavage of Cll (C2C), cartilage oligomeric matrix protein (COMP), hyaluronan (HA), high‐sensitive C‐reactive protein (hs‐CRP), and glycated serum protein (GSP)]. Three hand OA definitions were evaluated ‐ clinical ACR (American College of Rheumatology) and GOGO (Genetics of Generalized OA) criteria, and any single hand joint involvement. Non‐hand OA was defined as a negative hand examination for OA but varying prevalence of joint symptoms; the control group was defined as having neither symptoms nor evidence for clinical hand OA. Results: Mean In HA, In COMP, and In hs‐CRP were significantly higher in the hand OA group, compared with the non‐hand OA or control group. Adjusted for age and sex, mean In PIIANP (a collagen II synthesis marker) was significantly lower in the hand OA group compared with the other groups. Among those without clinical hand OA, GSP was associated with hand joint symptoms. Conclusions: This is the first report, to our knowledge, showing an association of OA biomarkers and hand OA based on physical examination alone. Analyses using these biomarkers as quantitative traits could reveal novel genetic loci and facilitate exploration of the genetic susceptibility to OA. Higher circulating hsCRP levels are associated with lower bone mineral density in healthy pre‐ and postmenopausal women: evidence for a link between systemic iflinflammati on and osteoporosis Jung‐Min Koh1, Young‐Ho Khang2, Chang‐Hee Jung1, Sungjin Bae1, Duk Jae Kim1, Yun‐ Ey Chung3 and Ghi Su Kim1 University of Ulsan College of Medicine, Republic of Korea Arthritis Research & Therapy 2008, 10:R27 • Factors involved in inflammation are linked with those critical for bone remodeling. We examined the association between serum high sensitivity C‐reactive protein (hsCRP) levels and bone mineral density (BMD) in healthy women. • Serum concentrations of hsCRP and total alkaline phosphatase (ALP) were measured in premenopausal ( n =3,662) and postmenopausal ( n =1,031) women aged 30 years or older. BMD was measured at the femoral neck and lumbar spine using dual energy X‐ray absorptiometry. According to the WHO definition, osteopenia was diagnosed at –2.5< T ‐score <–1.0 SD, and osteoporosis was diagnosed at T ‐score –2.5 SD at any sites. • Compared with normal subjects, log‐transformed serum hsCRP levels were higher in osteopenic and osteoporotic subjects (all, P <0.001) with linearity ( P for trend <0.001), after adjustment for age, BMI and menopausal status. Menopausal status did not have a significant interaction on the association ( P =0.457). In both premenopausal and postltmenopausal women, serum tttlotal ALP lllevels were hig her in the subjec ts with hig her hsCRP quintiles than those with the lowest quintile (all, P for trend <0.001). • Multivariate‐adjusted odds ratio (OR) for osteoporosis and osteopenia were 1.35 (95% CI, 1.08 to 1.68) in the highest hsCRP quintile of premenopausal women, and OR for osteoporosis was 1541.54 (95% CI, 1101.10 to 2.53) in the highest hsCRP quintile of postmenopausal women. • These findings suggest that subclinical systemic inflammation may be associated with bone turnover rate and bone mass in healthy women. Low‐Grade Inflammation May Be Present in Advanced Osteoarthritis Deanna M Green, PhD Annals of the Rheumatic Diseases 2004 Feb;63:2:200‐5

• Dr. Til Sturmer and colleagues at the German Centre for Research on Aging, Heidelberg, and University of Ulm, Germany. • The study included 770 patients with advanced hip and knee OA who underwent joint replacement. The mean age of these patients was 63 years, 63% were women, 51% were hypertensive, 45% used non‐ steroidal anti‐inflammatory drugs, 24% were taking diuretics, and 42% were former or current smokers. • Preoperative hsCRP levels were measured from frozen samples and analysed with respect to visual analogue scale (VAS) pain, Western Ontario and McMaster Universities OA index (WOMAC), and clinical and radiographic results. • Mean hsCRP concentration in these patients was significantly higher than that previously reported in 567 age and sex matched controls taken from a survey of healthy citizens in western Germany, 2.5 versus 1.7 mg/L (P < .0001). • Greater pain was significantly associated with higher mean hsCRP levels after adjusting for known or suspected predictors of increased hsCRP, including age, smoking, and body mass index. Specifically, a 5.7% increase in mean serum hsCRP was seen with every 100 mm increase on the VAS. Moreover, patients with at least one additional painful joint had a 17% higher mean hsCRP level than those without addition joint involvement (P = .02). • Smoking status had the greatest influence on hsCRP levels. Patients who currently smoked had a 92% higher mean hsCRP and those who formerly smoked had a 36% higher mean hsCRP than non‐smokers. Additional independent risk factors for higher mean hsCRP levels included older age, higher body mass index, female gender, and current regular use of diuretics. • Neither bilateral OA nor generalised OA were associated with mean hsCRP. Furthermore, no dimension on the WOMAC index was associated with mean hsCRP, not even the dimension of pain or any of the five pain items. • The authors conclude that "OA and the subjective severity of OA pain are associated with low level systemic inflammation as assessed by hsCRP in patients with advanced OA." OBESITY AS A RISK FACTOR FOR OSTEOARTHRITIS: MECHANICAL VERSUS METABOLIC Eaton, Charles B Medicine and Health Rhode Island, Jul 2004

Leptin is a low molecular weight 16‐kd protein produced and secreted primarily by visceral adipocytes. Plasma leptin correlates with fat mass and falls with weight loss. Most obese patients have high leptin concentrations, suggesting "leptin resistance" as a mechanism for obesity in many subjects. Leptin appears to act as a central regulator of appetite and energy expenditure through its effect on receptors in the hypothalamus , but it also appears to regulate metabolic activity in both bone and articular cartilage. Dummond has recently demonstrated that leptin can be detected in synovial fluid in patients with osteoarthritis, and that it can be produced locally by articular chondrocytes as well as osteophytic tissue.27 Further, when leptin was injected into rat joints, it stimulated expression of insulin‐ like growth factor‐1 and transforming growth factor B, with an accompanying increase in proteoglycan synthesis factors associated with bone and articular cartilage metabolism. Previous work by Figenschau showed that functional leptin receptors were detected in human adult chondrocytes, and treatment in vitro stimulated cell proliferation as well as matrix synthesis.28 The finding of leptin in osteophytic tissue and its ability to increase production of TGF‐B, a stimulator of osteophyte formation in OA, suggests that leptin could promote osteophyte formation in OA. If the role of leptin in the joint is one of promoting growth factors that maintain health and integrity of cartilage and bone, then leptin resistance at the level of the joint could lead to increased risk of OA. Severity and extent of osteoarthritis and low grade systemic inflammation as assessed by high sensitivity C reactive protein. StÃrmer T, Brenner H, Koenig W, GÃnther KP Ann Rheum Dis. 2004 Jun;63(6):750‐1 BACKGROUND: Although osteoarthritis (OA) is thought to derive from defective chondrocyte metabolism and thus inherently lack the large scale systemic response of rheumatoid arthritis, there is increasing interest in the acute phase proteins in OA. OBJECTIVE: To assess the association between high sensitivity C reactive protein (hsCRP) and severity and extent of OA in patients with advanced hip and knee OA. METHODS: Preoperative hsCRP was measured in frozen serum samples from 770 consecutive patients with hip or knee joint replacement due to advanced OA recruited between 1995 and 1996. Pain was measured by a visual analogue scale and the Western Ontario and McMaster Universities OA index (()WOMAC). The extent of OA in different joints was assessed clinically and radiographically. RESULTS: The (geometric) mean hsCRP was 2.5 mg/l among all patients. Severity of pain was associated with mean hsCRP (adjusted elevation highest v lowest quintile = 35%, p = 0.01) after controlling for known or suspected predictors of hsCRP, incldluding age, smoking, and bbdody mass index. Neither the bblilatera l nor the generalised extent of OA, nor any of the dimensions of the WOMAC were associated with mean hsCRP levels. CONCLUSIONS: Severity of pain, but not extent of OA, was associated with hsCRP levels in this group of patients with advanced OA. Longitudinal studies with repeated assessments of hsCRP and pain are needed to assess the possible value of hsCRP for monitoring or predicting the clinical course of OA. Interpretation of serum C‐reactive protein (CRP) levels for cardiovascular disease risk is complicated by race, pulmonary disease, body mass index, gender, and osteoarthiihritis V. Kraus, T. Stabler, G. Luta, J. Renner, A. Dragomir, J. Jordan Osteoarthritis and Cartilage 2007, Volume 15, Issue 8, Pages 966‐971 Objective ‐ High‐sensitivity C‐reactive protein (hsCRP) in serum is used as a marker of risk for cardiovascu lar disease (CVD); however CRP is a non‐specific acute phase reactant. We evaldluated the association between hsCRP concentrations and the most common form of arthritis, osteoarthritis (OA), and assessed the applicability of hsCRP for CVD risk prediction. Methods ‐ Participants (n=662) were selected from the population‐based Johnston County Osteoarthritis Project, using stratified simple random sampling to achieve balance according to radiographic knee OA status, ethnic group, gender, and age group. The presence and severity of knee and hip OA were determined radiographically. CVD risk was estimated by hsCRP concentration and independently with the Framingham risk algorithm. Results ‐ Serum natural log‐transformed hsCRP (ln hsCRP) was higher in African‐Americans (P<0.0001) and women (P<0.0001), was higher in participants who had chronic pulmonary disease (P=0.01), hypertension (P<0.0001), or used pain medications (P=0.004), and correlated with body mass index (BMI) (r=0.40, P<0.0001) and waist circumference (r=0.33, P<0.0001), but not with age, CVD, or current smoking. Ln hsCRP was strongly positively associated with all definitions of radiographic OA (rOA; P<0.0001), but this association was not independent of BMI. Although 183 participants reported no CVD and were classified as low risk by the Framingham CVD score, 61% of them were classified as moderate or high risk for CVD using hsCRP; this proportion designated high risk for CVD on the basis of hsCRP consisted primarily of women (P<0.05) and individuals with OA (P<0.01). Conclusions ‐ The pathogenic significance of hsCRP elevations in this subgroup is unclear. Serum hsCRP for predicting risk of CVD is confounded by obesity, ethnicity, gender and comorbidities. ROSENBERG COOLEY METCALF THE ORTHOPEDIC CLINIC AT PARK CITY

900 Round Valley Drive • Park City, Utah 84060 • Tel: 435‐655‐6600 rcmclinic.com 62 yo female LCRPOALow CRP OA Low CRP OA Low CRP OA Low CRP OA Low CRP OA Low CRP OA 62 yo female Hihigh CRP OA High CRP OA High CRP OA High CRP OA High CRP OA Basic Dietary Principles

The intent of this section is to show a spectrum of ideas that are in ciilirculation. It is not to endorse anything more than common sense. Pro Health Lab ProHealthLab.org 900 Round Valley Dr., suite 250, Park City, UT 84060 Established by Thomas Rosenberg, MD, et. Al.

AiAnti‐IflInflammatory FFdoods IflInflammatory FdFoods • Ginger, garlic, turmeric, cumin, etc. • Soda, sugary juices, etc. • Fruits (bright colors often best) • Trans fats • Vegetables (dark colors often best) • High glycemic carbs, e.g. white • Fish (salmon, halibut, trout, etc.) bread, white rice, sugar • Soy Protein (tofu, soy milk, etc.) • Immoderate amounts of alcohol • Legumes (plants with pods) • Processed meats/foods • Seaweed (sea vegetables) • Most Desserts • RdRed wii/ne/grape seeds • Animal fats • Olive and canola oil • Most cheeses • Green tea • Fried foods • Lean meats • Feedlot cattle • Low‐fat dairy • Milk chocolate Pro Health Lab – continued A 501(c)3 Non‐profit Organization

Supplementary nutrition Summary Partly because healthy organic • You are in charge. foods can be difficult to obtain, we • Choose anti‐inflammatory foods recommend the multi‐ and bail out on inflammatory food system/multi‐nutrient choices. supplements Nutriex Sport (hig her • demand) and Nutriex Health Take advantage of supplementary (maintenance). We also nutrition (e.g. Nutriex Sport and recommend Nutriex Omega 3/fish Fish Oil). oil whhhich ffhurther reduces • Factor time into the equation. inflammation by improving • Monitor hs‐CRP improvements by essential fatty acid bio‐chemistry testing every 3, 6 or 12 months. throughout your organ systems. • Set goals to reduce ppprescription Early homo sapiens drugs wisely, if possible (your MD thrived on fresh water needs to be on board). fish and their amazing • Observe yourself for improvements brains developed in sleep, mood, BMI, blood pressure, breathing, joint partly due to this diet. pain/function, skin color, etc. The China Study T. CliColin CbllCampbell, PhD and Thomas M. CbllCampbell II BenBella Books, Inc 2006 • Recommends ~10% of total calories from protein and only 10% of the 10% (1%) from animal‐based foods. This is based on analysis of the health factors of the common diet consumed in China. • Commonly in US diets 15‐17% of total calories is provided by protein and upwards of 80% of this protein is animal‐based. • By analyzing the data, the authors believe this type of diet would sigygnificantly reduce many types of chronic disease. Nourishing Traditions Sally Fallon www.westonaprice.org

• Eat whole, unprocessed foods. The diets of healthy, nonindustrialized peoples contain no refined or denatured foods or ingredients, such as refined sugar or high fructose corn syrup; white flour; canned foods; pasteurized, homogenized, skim or low fat milk; refined or hydrogenated vegetable oils; protein powders; artificial vitamins; or toxic additives and colorings. • Recommends a traditional diet high in animal fat, she is particularly fond of butter. Use traditional vegetable oils only‐‐extra virgin olive oil, expeller‐expressed sesame oil, small amounts of expeller‐expressed flax oil, and the tropical oils‐‐coconut oil, palm oil and palm kernel oil. • Raw Milk: Back in the 20s, Americans could buy fresh raw whole milk, real clabber and buttermilk, luscious naturally yellow butter, fresh farm cheeses and cream in various colors and thicknesses. Today's milk is accused of causing everything from allergies to heart disease, to cancer, but when Americans could buy Real Milk, these diseases were rare. • Avoid commercially processed ffdoods such as cookies, cakes, crackers, TV dinners, soft drinks, packaged sauce mixes, etc. Read labels! • Confused About Soy?‐Traditionally soy is eaten in small amounts of fermented Tempe or Tofu. High levels of phytic acid in unfermented soy reduce assimilation of calcium, magnesium, copper, iron and zinc. Soy milk is made from the by‐products of soy beans after pressed for oil. The Scepter Nutrition Program for elite athletes Deborah M. Westphal, RPh, BCNSP (Registered Pharmacist, Board Certified Nutrition Support Pharmacist) The Scepter Diet: Meal Examples Ms. WthlWestphal iildncludes a lltot of LUNCH Main dish salad avocado, olives, and a wide with avocado, organic variety of fruits and vegetables, sprouted macadamia nuts. bison, turkey bacon, salmon, eggs, etc.

DINNER Fried organic chicken (macadamia nut Gazpacho or raw vegetable oil + pasture butter and no flour = no starch), soup made in whole food asparagus, cauliflower and green salad with blender. This is yellow tomato balsamic vinegar and (olive oil) dressing. and yellow bell pepper soup. Eat Right For Your (Blood) Type Dr. Peter J. D’Adamo, naturopathic physician G.P, Putnam’s Sons • If you're blood type O ("for old," as in humanity's oldest blood line) your digestive tract retains the memory of ancient times, says D'Adamo, so you're metabolism will benefit from lean meats, poultry (chicken is neutral), and fish. You're advised to restrict grains, breads, and legumes, and to enjoy vigorous exercise. • Type A ("for agrarian") flourishes on vegetarian diets, "the inheritance of their more settle d and less warlike farmer ancest"tors," says D'Adamo. The type A die t contitains soy proteins, grains, and organic vegetables and encourages gentle exercise. • The nomadic blood type B has a tolerant digestive system and can enjoy low‐fat dairy, meat, and produce but, among other things, should avoid wheat, corn, and lentils, D'Adamo says. If you're type B, it's recommended you exercise moderately. • The "modern" blood type AB has a sensitive digestive tract and should avoid chicken, beef, and pork but enjoy seafood, tofu, dairy, and most produce. The fitness regimen for ABs is calming exercises. • What a Diet Expert Says: "Within the diet itself are generally good diet recommendations," says David W. Grotto, RD, LD, a spokesman for the American Dietetic Association. "DDAdamo'Adamo doesn' t say avoid vegetables and fruit, for example ‐‐ but his specific recommendations based on blood type ‐‐ the science is not there to support it. I'm not aware that anyone has duplicated his research." DEFLAME No Nonsense Nutrition For Inflammation Reduction www.deflame.com • Dietary arachidonic acid converts into inflammation‐ and pain‐producing PGE2,.Clearly we should limit our dietary intake of arachidonic/PGE2. • We accumulate arachidonic acid in two ways. First, we consume it directly whenever we eat grain/corn fed animals. Grains and corn contain linoleic acid, which when consumed by animals is converted into arachidonic acid. Modern grain/corn‐fed domestic meat can up to 25% fat by weight compared to about 5% in wild game (5). Our over‐fat meat, or obese meat, is a source of extra arachidonic acid. About 15‐20% of the average American’s diet comes from arachidonic acid‐rich animal products. • Second, like animals, whenever we humans consume grains and corn, we convert the lino le ic acid itinto arachidon ic acid. We also consume excessive amounts of seed oils (corn, safflower, sunflower, and cottonseed oils), which contain mostly linoleic acid. Peanut and soybean oils are also high in linoleic acid. Americans consume approximately 60 pounds of these omega‐6 oils each year (7), which can convert into pain and inflammation producing arachidonic acid/PGE2. In contrast, back in 1900, we consumed about 15 pounds per year (7). • As mentioned earlier, linoleic and arachidonic acids are omega‐6 fatty acids. These need to be consumed in modest quantities and in balance with the anti‐inflammatory omega‐3 fatty acids. • Ideally a 1:1 ratio of omega‐6 (n‐6) to omega‐3 (n‐3) fatty acids is best, and less than 4:1 is acceptable (6). Below are two tables that contain n‐6:n‐3 ratios in common foods. Foods with anti-inflammatory DEFLAME Nutrition Continued ratios

Food n-6:n-3 Ratio Foods with pro-inflammatory ratios Fruit 3:1 or better n-6:n-3 Green Food 1:1 Ratio vegetables Nuts 5:1 or worse White 3:1 potato Grain-fed meat 5:1 or worse Sweet 4:1 potato Grain-fed chicken (white meat) 15:1 Grass-fed 3-5:1 meat Grain-fed chicken (dark meat) 17:1 Wild game 3:1 or better Grains (wheat, rye, oats, rice, 20:1 Fresh fish 1:1 or better barley, etc.) Farmed- Potato chips raised 1:1 or worse (and similar foods with added 60:1 or worse salmon n-6 seed oils) Flax seeds 1:3.6 n-6 Seeds and seed oils (corn, sunflower, safflower, 70:1 or worse Hemp seeds 2.5:1 cottonseed, peanut) Chia seeds 1:3 Sometimes it is easy to loose track…

Park City Mountain Resort Jupiter Bowl My Personal Big Nots

• High fructose corn syyprup • Artificial sweeteners • Hydrogenated or partially hydrogenated vegetable oils • Excessive added sugar • Artificial food additives, especially MSG, hydrolyzed vegetbltable prottiein and aspartame, whic h are neurotoxins* and other unrecognizable chemicals

Read labels, these can be hard to avoid! *Weston A. Price Foundation Mindful or Conscious Eating

• Be aware of what you eat. • Give it your full attention and savor the food. • Avoid distractions such as watching TV and reading while eating. • When your mind wanders and you stop tasting, it is time to stop eating. • You’ll be satisfied with less. 80% ‐ 20% Rule

• 80% try to do what is a healthy diet for you. • 20% don’t worry about it too much. • Don’t let excessive concern take away the joy of food. “You will remember when to eat was a pleasure” Kansas, Leftoverture, Carry On Wayward Son, 1976

Personally, I am an opportunivor. Exercise: I encourage people to find activities that nourish their soul at best, or at least, activities they don’t hate. Summary of Dietary Recommendations

Eat food, Not too much, Mostly plants Michael Pollan